bims-cesiha Biomed News
on Cell signalling in the heart
Issue of 2021‒02‒14
fifty-four papers selected by
Danae Angelidaki
Max Planck Institute for Biology of Ageing
  1. GRK5 contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.
  2. A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload.
  3. Activation of Nrf2 by miR-152 Inhibits Doxorubicin-Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis.
  4. Different roles of BAG3 in cardiac physiological hypertrophy and pathological remodeling.
  5. Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy.
  6. Mechanotranduction Pathways in the Regulation of Mitochondrial Homeostasis in Cardiomyocytes.
  7. Angiotensin II receptor 1 controls profibrotic Wnt/β-catenin signalling in experimentalautoimmune myocarditis.
  8. AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.
  9. AMPK/SIRT1 Pathway is Involved in Arctigenin-Mediated Protective Effects Against Myocardial Ischemia-Reperfusion Injury.
  10. Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart.
  11. Rosmarinic acid ameliorated cardiac dysfunction and mitochondrial injury in diabetic cardiomyopathy mice via activation of the SIRT1/PGC-1α pathway.
  12. CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor.
  13. FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K.
  14. The protective effects of the miR-129-5p/keap-1/Nrf2 axis on Ang II-induced cardiomyocyte hypertrophy.
  15. Specific protein 1 inhibitor mithramycin A protects cardiomyocytes from myocardial infarction via interacting with PARP.
  16. The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction.
  17. BGP-15 Protects against Heart Failure by Enhanced Mitochondrial Biogenesis and Decreased Fibrotic Remodelling in Spontaneously Hypertensive Rats.
  18. Novel roles of an intragenic G-quadruplex in controlling microRNA expression and cardiac function.
  19. Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress.
  20. Qingda granule attenuates cardiac fibrosis via suppression of the TGF-β1/Smad2/3 signaling pathway in vitro and in vivo.
  21. Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload.
  22. Effects of PPARγ agonist pioglitazone on cardiac fibrosis in diabetic mice by regulating PTEN/AKT/FAK pathway.
  23. Forskolin Protected against Streptozotocin-Induced Diabetic Cardiomyopathy via Inhibition of Oxidative Stress and Cardiac Fibrosis in Mice.
  24. Empagliflozin and Liraglutide Differentially Modulate Cardiac Metabolism in Diabetic Cardiomyopathy in Rats.
  25. GPR39 promotes cardiac hypertrophy by regulating the AMPK-mTOR pathway and protein synthesis.
  26. Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes.
  27. Ferroptosis and its emerging roles in cardiovascular diseases.
  28. Paeonol Protects Against Myocardial Ischemia/Reperfusion-Induced Injury by Mediating Apoptosis and Autophagy Crosstalk.
  29. LGR4 silence aggravates ischemic injury by modulating mitochondrial function and oxidative stress via ERK signaling pathway in H9c2 cells.
  30. Loss of endothelial cell-specific autophagy-related protein 7 exacerbates doxorubicin-induced cardiotoxicity.
  31. IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury.
  32. LncRNA ZNF593-AS Alleviates Contractile Dysfunction in Dilated Cardiomyopathy.
  33. Development of an AAV9-RNAi-mediated silencing strategy to abrogate TRPM4 expression in the adult heart.
  34. Computational modeling approaches to cAMP/PKA signaling in cardiomyocytes.
  35. Protective effects of NLRP3 inhibitor MCC950 on sepsis-induced myocardial dysfunction.
  36. Growth differentiation factor 11 mitigates cardiac radiotoxicity via activating AMPKα.
  37. Scutellarin protects against diabetic cardiomyopathy via inhibiting oxidative stress and inflammatory response in mice.
  38. Metformin Reverses the Enhanced Myocardial SR/ER-Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice.
  39. Protective effect of MAPK signaling pathway mediated by ITGB3 gene silencing on myocardial ischemia-reperfusion injury in mice and its mechanism.
  40. Elevated MST1 leads to apoptosis via depletion of YAP1 in cardiomyocytes exposed to high glucose.
  41. Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players.
  42. The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure.
  43. Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein.
  44. Smad4 regulates the nuclear translocation of Nkx2-5 in cardiac differentiation.
  45. Rad-GTPase contributes to heart rate via L-type calcium channel regulation.
  46. Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates.
  47. Role of prostaglandin E2 in allogeneic mesenchymal stem cell therapy for cardiac repair.
  48. β1-adrenergic receptor N-terminal cleavage by ADAM17; the mechanism for redox-dependent downregulation of cardiomyocyte β1-adrenergic receptors.
  49. Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome.
  50. Wnt Signaling Plays a Key Role in the Regulation of the Immune Response and Cardiac Damage during Trypanosoma cruzi Infection.
  51. Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis.
  52. Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes.
  53. The role of glucose in physiological and pathological heart formation.
  54. Role of Oxidative Stress in the Mechanisms of Anthracycline-Induced Cardiotoxicity: Effects of Preventive Strategies.
  1. Cardiovasc Res. 2021 Feb 09. pii: cvab044. [Epub ahead of print]
    GRK5 contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.
    Claudio de Lucia, Laurel A Grisanti, Giulia Borghetti, Michela Piedepalumbo, Jessica Ibetti, Anna Maria Lucchese, Eric W Barr, Rajika Roy, Ama Dedo Okyere, Haley Christine Murphy, Erhe Gao, Giuseppe Rengo, Steven R Houser, Douglas G Tilley, Walter J Koch.
      AIMS: Myocardial infarction (MI) is the most common cause of heart failure (HF) worldwide. G protein-coupled receptor kinase 5 (GRK5) is upregulated in failing human myocardium and promotes maladaptive cardiac hypertrophy in animal models. However, the role of GRK5 in ischemic heart disease is still unknown. In this study, we evaluated whether myocardial GRK5 plays a critical role post-MI in mice and included examination of specific cardiac immune and inflammatory responses.METHODS AND RESULTS: Cardiomyocyte-specific GRK5 overexpressing transgenic mice (TgGRK5) and non-transgenic littermate control (NLC) mice as well as cardiomyocyte-specific GRK5 knockout mice (GRK5cKO) and wild type (WT) were subjected to MI and, functional as well as structural changes together with outcomes were studied. TgGRK5 post-MI mice showed decreased cardiac function, augmented left ventricular dimension and decreased survival rate compared to NLC post-MI mice. Cardiac hypertrophy and fibrosis as well as fetal gene expression were increased post-MI in TgGRK5 compared to NLC mice. In TgGRK5 mice, GRK5 elevation produced immuno-regulators that contributed to the elevated and long-lasting leukocyte recruitment into the injured heart and ultimately to chronic cardiac inflammation. We found an increased presence of pro-inflammatory neutrophils and macrophages as well as neutrophils, macrophages and T- lymphocytes at 4- days and 8- weeks respectively post-MI in TgGRK5 hearts. Conversely, GRK5cKO mice were protected from ischemic injury and showed reduced early immune cell recruitment (predominantly monocytes) to the heart, improved contractility and reduced mortality compared to WT post-MI mice. Interestingly, cardiomyocyte-specific GRK2 transgenic mice did not share the same phenotype of TgGRK5 mice and did not have increased cardiac leukocyte migration and cytokine or chemokine production post-MI.
    CONCLUSIONS: Our study shows that myocyte GRK5 has a crucial and GRK-selective role on the regulation of leucocyte infiltration into the heart, cardiac function and survival in a murine model of post-ischemic HF, supporting GRK5 inhibition as a therapeutic target for HF.
    TRANSLATIONAL PERSPECTIVE: GRK5 is upregulated in failing human myocardium and associated with heart failure development. In this study, we evaluated whether cardiomyocyte GRK5 plays a critical role during ischemic heart disease in a mouse animal model. We discovered that GRK5 overexpression in cardiomyocyte affects cardiac function, remodeling, immune cell recruitment, and ultimately survival in ischemic heart failure. Conversely, cardiomyocyte-specific GRK5 ablation diminished the early immune cell infiltration in the heart, improved contractility and reduced mortality post-myocardial infarction. The overall translational significance of these findings is substantial, as selective small molecule inhibitors of GRK5 have begun to emerge as novel therapeutic treatment in heart disease.
    Keywords:  cardiac remodeling; immune system; ischemic heart failure; left ventricle; myocardial ischemia
    DOI:  https://doi.org/10.1093/cvr/cvab044
  2. J Mol Cell Cardiol. 2021 Feb 03. pii: S0022-2828(21)00019-5. [Epub ahead of print]
    A peptide of the amino-terminus of GRK2 induces hypertrophy and yet elicits cardioprotection after pressure overload.
    Kamila M Bledzka, Iyad H Manaserh, Jessica Grondolsky, Jessica Pfleger, Rajika Roy, Erhe Gao, J Kurt Chuprun, Walter J Koch, Sarah M Schumacher.
      G protein-coupled receptor (GPCR) kinase 2 (GRK2) expression and activity are elevated early on in response to several forms of cardiovascular stress and are a hallmark of heart failure. Interestingly, though, in addition to its well-characterized role in regulating GPCRs, mounting evidence suggests a GRK2 "interactome" that underlies a great diversity in its functional roles. Several such GRK2 interacting partners are important for adaptive and maladaptive myocyte growth; therefore, an understanding of domain-specific interactions with signaling and regulatory molecules could lead to novel targets for heart failure therapy. Herein, we subjected transgenic mice with cardiac restricted expression of a short, amino terminal fragment of GRK2 (βARKnt) to pressure overload and found that unlike their littermate controls or previous GRK2 fragments, they exhibited an increased left ventricular wall thickness and mass prior to cardiac stress that underwent proportional hypertrophic growth to controls after acute pressure overload. Importantly, despite this enlarged heart, βARKnt mice did not undergo the expected transition to heart failure observed in controls. Further, βARKnt expression limited adverse left ventricular remodeling and increased cell survival signaling. Proteomic analysis to identify βARKnt binding partners that may underlie the improved cardiovascular phenotype uncovered a selective functional interaction of both endogenous GRK2 and βARKnt with AKT substrate of 160 kDa (AS160). AS160 has emerged as a key downstream regulator of insulin signaling, integrating physiological and metabolic cues to couple energy demand to membrane recruitment of Glut4. Our preliminary data indicate that in βARKnt mice, cardiomyocyte insulin signaling is improved during stress, with a coordinate increase in spare respiratory activity and ATP production without metabolite switching. Surprisingly, these studies also revealed a significant decrease in gonadal fat weight, equivalent to human abdominal fat, in male βARKnt mice at baseline and following cardiac stress. These data suggest that the enhanced AS160-mediated signaling in the βARKnt mice may ameliorate pathological cardiac remodeling through direct modulation of insulin signaling within cardiomyocytes, and translate these to beneficial effects on systemic metabolism.
    Keywords:  GRK2; Heart failure; Hypertrophy; Physiological; Proteomics
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.01.004
  3. Oxid Med Cell Longev. 2021 ;2021 8860883
    Activation of Nrf2 by miR-152 Inhibits Doxorubicin-Induced Cardiotoxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis.
    Wen-Bin Zhang, Xin Lai, Xu-Feng Guo.
      Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.
    DOI:  https://doi.org/10.1155/2021/8860883
  4. Transl Res. 2021 Feb 09. pii: S1931-5244(21)00027-X. [Epub ahead of print]
    Different roles of BAG3 in cardiac physiological hypertrophy and pathological remodeling.
    Pengyu Jia, Nan Wu, Huimin Yang, Yuxuan Guo, Xiaofan Guo, Yingxian Sun.
      Heart failure is one of the leading causes of death worldwide. A stimulated heart undergoes either adaptive physiological hypertrophy, which can maintain a normal heart function, or maladaptive pathological remodeling, which can deteriorate heart function. These two kinds of remodeling often co-occur at the early stages of many heart diseases and have important effects on cardiac function. The Bcl2-associated athanogene 3 (BAG3) protein is highly expressed in the heart and has many functions. However, it is unknown how BAG3 is regulated and what its function is during physiological hypertrophy and pathological remodeling. We generated tamoxifen-induced, heart-specific heterozygous and homozygous BAG3 knockout mouse models (BAG3 protein level decreased by approximately 40% and 80% in the hearts after tamoxifen administration). BAG3 knockout models were subjected to swimming training or phenylephrine (PE) infusion to induce cardiac physiological hypertrophy and pathological remodeling. Neonatal rat ventricular cardiomyocytes (NRVCs) were used to study BAG3 functions and mechanisms in vitro. We found that BAG3 was upregulated in physiological hypertrophy and in pathological remodeling both in vivo and in vitro. Heterozygous or homozygous knockout BAG3 in mouse hearts and knockdown of BAG3 in the NRVCs blunted physiological hypertrophy and aggravated pathological remodeling, while overexpression of BAG3 promoted physiological hypertrophy and inhibited pathological remodeling in NRVCs. Mechanistically, BAG3 overexpression in NRVCs promoted physiological hypertrophy by activating the protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway. BAG3 knockdown in NRVCs aggravated pathological remodeling through activation of the calcineurin/nuclear factor of activated T cells 2 (NFATc2) pathway. Because BAG3 has a dual role in cardiac remodeling, heart-specific regulation of BAG3 may be an effective therapeutic strategy to protect against deterioration of heart function and heart failure caused by many heart diseases.
    Keywords:  Akt/mTOR pathway; BAG3; Calcineurin/NFAT(c2) pathway; Pathological remodeling; Physiological hypertrophy
    DOI:  https://doi.org/10.1016/j.trsl.2021.02.004
  5. Front Cell Dev Biol. 2020 ;8 628842
    Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy.
    Xinyu Feng, Shanjie Wang, Xingjun Yang, Jie Lin, Wanrong Man, Yuan Dong, Yan Zhang, Zhijing Zhao, Haichang Wang, Dongdong Sun.
      The disruption of mitochondrial dynamics is responsible for the development of diabetic cardiomyopathy (DCM). However, the mechanisms that regulate the balance of mitochondrial fission and fusion are not well-understood. Wild-type, Mst1 transgenic and Mst1 knockout mice were induced with experimental diabetes by streptozotocin injection. In addition, primary neonatal cardiomyocytes were isolated and cultured to simulate diabetes to explore the mechanisms. Echocardiograms and hemodynamic measurements revealed that Mst1 knockout alleviated left ventricular remodeling and cardiac dysfunction in diabetic mice. Mst1 knockdown significantly decreased the number of TUNEL-positive cardiomyocytes subjected to high-glucose (HG) medium culture. Immunofluorescence study indicated that Mst1 overexpression enhanced, while Mst1 knockdown mitigated mitochondrial fission in DCM. Mst1 participated in the regulation of mitochondrial fission by upregulating the expression of Drp1, activating Drp1S616 phosphorylation and Drp1S637 dephosphorylation, as well as promoting Drp1 recruitment to the mitochondria. Furthermore, Drp1 knockdown abolished the effects of Mst1 on mitochondrial fission, mitochondrial membrane potential and mitochondrial dysfunction in cardiomyocytes subjected to HG treatment. These results indicated that Mst1 knockout inhibits mitochondrial fission and alleviates left ventricular remodeling thus prevents the development of DCM.
    Keywords:  DCM; Diabetic Cardiomyopathy; Mammalian Sterile 20-like Kinase 1; Mitochondrial Dysfunction; Mitochondrial Fission; Mitochondrial Fusion; Mst1
    DOI:  https://doi.org/10.3389/fcell.2020.628842
  6. Front Cell Dev Biol. 2020 ;8 625089
    Mechanotranduction Pathways in the Regulation of Mitochondrial Homeostasis in Cardiomyocytes.
    Hongyu Liao, Yan Qi, Yida Ye, Peng Yue, Donghui Zhang, Yifei Li.
      Mitochondria are one of the most important organelles in cardiomyocytes. Mitochondrial homeostasis is necessary for the maintenance of normal heart function. Mitochondria perform four major biological processes in cardiomyocytes: mitochondrial dynamics, metabolic regulation, Ca2+ handling, and redox generation. Additionally, the cardiovascular system is quite sensitive in responding to changes in mechanical stress from internal and external environments. Several mechanotransduction pathways are involved in regulating the physiological and pathophysiological status of cardiomyocytes. Typically, the extracellular matrix generates a stress-loading gradient, which can be sensed by sensors located in cellular membranes, including biophysical and biochemical sensors. In subsequent stages, stress stimulation would regulate the transcription of mitochondrial related genes through intracellular transduction pathways. Emerging evidence reveals that mechanotransduction pathways have greatly impacted the regulation of mitochondrial homeostasis. Excessive mechanical stress loading contributes to impairing mitochondrial function, leading to cardiac disorder. Therefore, the concept of restoring mitochondrial function by shutting down the excessive mechanotransduction pathways is a promising therapeutic strategy for cardiovascular diseases. Recently, viral and non-viral protocols have shown potentials in application of gene therapy. This review examines the biological process of mechanotransduction pathways in regulating mitochondrial function in response to mechanical stress during the development of cardiomyopathy and heart failure. We also summarize gene therapy delivery protocols to explore treatments based on mechanical stress-induced mitochondrial dysfunction, to provide new integrative insights into cardiovascular diseases.
    Keywords:  cardiac maturation; heart development; mechanotransduction pathway; mitochondrial disorder; mitochondrial homeostasis
    DOI:  https://doi.org/10.3389/fcell.2020.625089
  7. Cardiovasc Res. 2021 Feb 12. pii: cvab039. [Epub ahead of print]
    Angiotensin II receptor 1 controls profibrotic Wnt/β-catenin signalling in experimentalautoimmune myocarditis.
    Marcin Czepiel, Dario Diviani, Agnieszka Jaźwa-Kusior, Karolina Tkacz, Filip Rolski, Ryszard T Smolenski, Maciej Siedlar, Urs Eriksson, Gabriela Kania, Przemysław Błyszczuk.
      AIMS: Angiotensin (Ang) II signalling has been suggested to promote cardiac fibrosis in inflammatory heart diseases, however the underlaying mechanisms remain obscure. Using Agtr1a-/- mice with genetic deletion of angiotensin receptor type 1 (ATR1) and the experimental autoimmune myocarditis (EAM) model, we aimed to elucidate the role of Ang II-ATR1 pathway in development of heart-specific autoimmunity and post-inflammatory fibrosis.METHODS AND RESULTS: EAM was induced in wild-type (WT) and Agtr1a-/- mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Agtr1a-/- mice developed myocarditis to a similar extent as WT controls at day 21, but showed reduced fibrosis and better systolic function at day 40. Crisscross bone marrow chimera experiments proved that ATR1 signalling in the bone-marrow compartment was critical for cardiac fibrosis. Heart infiltrating, bone-marrow derived cells produced Ang II, but lack of ATR1 in these cells reduced transforming growth factor beta (TGF-β) mediated fibrotic responses. At the molecular level, Agtr1a-/- heart-inflammatory cells showed impaired TGF-β-mediated phosphorylation of Smad2 and TAK1. In WT cells, TGF-β induced formation of RhoA-GTP and RhoA-A-kinase anchoring protein-Lbc (AKAP-Lbc) complex. In Agtr1a-/- cells stabilization of RhoA-GTP and interaction of RhoA with AKAP-Lbc were largely impaired. Furthermore, in contrast to WT cells, Agtr1a-/- cells stimulated with TGF-β failed to activate canonical Wnt pathway indicated by suppressed activity of glycogen synthase kinase-3 (GSK-3)β and nuclear β-catenin translocation and showed reduced expression of Wnts. In line with these in vitro findings, β-catenin was detected in inflammatory regions of hearts of WT, but not Agtr1a-/- mice and expression of canonical Wnt1 and Wnt10b were lower in Agtr1a-/- hearts.
    CONCLUSIONS: Ang II-ATR1 signalling is critical for development of postinflammatory fibrotic remodelling and dilated cardiomyopathy. Our data underpins the importance of Ang II-ATR1 in effective TGF-β downstream signalling response including activation of profibrotic Wnt/β-catenin pathway.
    TRANSLATIONAL PERSPECTIVE: Myocardial fibrosis causes impaired cardiac function in inflammatory heart diseases. It has been believed that targeting angiotensin II receptor 1 (ATR1) could not only lower blood pressure, but also effectively block both, immune and fibrotic processes in the heart. By using an experimental autoimmune myocarditis model and ATR1-deficient mice, we show that the specific ATR-dependent mechanism is rather limited to control profibrotic, but not inflammatory response. On the molecular level, ATR1 plays a central role in activation of the canonical Wnt pathway in profibrotic response. Thus, these data help to understand how the actual angiotensin II-ATR1 signalling contributes to immunofibrotic heart diseases.
    Keywords:  TGF-β; Wnt; angiotensin II; angiotensin II receptor 1; cardiac fibrosis; experimental autoimmune myocarditis; inflammatory cells; signalling
    DOI:  https://doi.org/10.1093/cvr/cvab039
  8. Basic Res Cardiol. 2021 Feb 09. 116(1): 10
    AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.
    Cécile Dufeys, Evangelos-Panagiotis Daskalopoulos, Diego Castanares-Zapatero, Simon J Conway, Audrey Ginion, Caroline Bouzin, Jérôme Ambroise, Bertrand Bearzatto, Jean-Luc Gala, Stephane Heymans, Anna-Pia Papageorgiou, Stefan Vinckier, Julien Cumps, Jean-Luc Balligand, Maarten Vanhaverbeke, Peter Sinnaeve, Stefan Janssens, Luc Bertrand, Christophe Beauloye, Sandrine Horman.
      We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.
    Keywords:  AMPKα1; Cardiac fibroblast; Cardiac fibrosis; Connexin 43; Myofibroblast; miR-125b-5p
    DOI:  https://doi.org/10.1007/s00395-021-00846-y
  9. Front Pharmacol. 2020 ;11 616813
    AMPK/SIRT1 Pathway is Involved in Arctigenin-Mediated Protective Effects Against Myocardial Ischemia-Reperfusion Injury.
    Cheng-Yin Liu, Yi Zhou, Tao Chen, Jing-Chao Lei, Xue-Jun Jiang.
      Arctigenin, one of the active ingredients extracted from Great Burdock (Arctium lappa) Achene, has been found to relieve myocardial infarction injury. However, the specific mechanism of Arctigenin against myocardial infarction remains largely unknown. Here, both acute myocardial ischemia-reperfusion injury (AMI/R) rat model and oxygen glucose deprivation (OGD)-induced myocardial cell injury model were constructed to explore the underlying role of AMPK/SIRT1 pathway in Arctigenin-mediated effects. The experimental data in our study demonstrated that Arctigenin ameliorated OGD-mediated cardiomyocytes apoptosis, inflammation and oxidative stress in a dose-dependent manner. Besides, Arctigenin activated AMPK/SIRT1 pathway and downregulated NF-κB phosphorylation in OGD-treated cardiomyocytes, while inhibiting AMPK or SIRT1 by the Compound C (an AMPK inhibitor) or SIRT1-IN-1 (a SIRT1 inhibitor) significantly attenuated Arctigenin-exerted protective effects on cardiomyocytes. In the animal experiments, Arctigenin improved the heart functions and decreased infarct size of the AMI/R-rats, accompanied with downregulated oxidative stress, inflammation and apoptotic levels in the heart tissues. What's more, Arctigenin enhanced the AMPK/SIRT1 pathway and repressed NF-κB pathway activation. Taken together, our data indicated that Arctigenin reduced cardiomyocytes apoptosis against AMI/R-induced oxidative stress and inflammation at least via AMPK/SIRT1 pathway.
    Keywords:  AMPK/SIRT1 pathway; arctigenin; inflammation; myocardial infarction; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2020.616813
  10. Cardiovasc Res. 2021 Feb 08. pii: cvab043. [Epub ahead of print]
    Fine-tuning the cardiac O-GlcNAcylation regulatory enzymes governs the functional and structural phenotype of the diabetic heart.
    Darnel Prakoso, Shiang Y Lim, Jeffrey R Erickson, Rachel S Wallace, Jarmon G Lees, Mitchel Tate, Helen Kiriazis, Daniel G Donner, Darren C Henstridge, Jonathan R Davey, Hongwei Qian, Minh Deo, Laura J Parry, Amy J Davidoff, Paul Gregorevic, John C Chatham, Miles J De Blasio, Rebecca H Ritchie.
      AIMS: The glucose-driven enzymatic modification of myocardial proteins by the sugar moiety, β-N-acetylglucosamine (O-GlcNAc), is increased in pre-clinical models of diabetes, implicating protein O-GlcNAc modification in diabetes-induced heart failure. Our aim was to specifically examine cardiac manipulation of the two regulatory enzymes of this process on the cardiac phenotype, in the presence and absence of diabetes, utilising cardiac-targeted recombinant-adeno-associated viral-vector-6 (rAAV6)-mediated gene delivery.METHODS AND RESULTS: In human myocardium, total protein O-GlcNAc modification was elevated in diabetic relative to non-diabetic patients, and correlated with left ventricular (LV) dysfunction. The impact of rAAV6-delivered O-GlcNAc transferase (rAAV6-OGT, facilitating protein O-GlcNAcylation), O-GlcNAcase (rAAV6-OGA, facilitating de-O-GlcNAcylation) and empty vector (null) were determined in non-diabetic and diabetic mice. In non-diabetic mice, rAAV6-OGT was sufficient to impair LV diastolic function and induce maladaptive cardiac remodelling, including cardiac fibrosis and increased Myh-7 and Nppa pro-hypertrophic gene expression, recapitulating characteristics of diabetic cardiomyopathy. In contrast, rAAV6-OGA (but not rAAV6-OGT) rescued LV diastolic function and adverse cardiac remodelling in diabetic mice. Molecular insights implicated impaired cardiac PI3K(p110α)-Akt signalling as a potential contributing mechanism to the detrimental consequences of rAAV6-OGT in vivo. In contrast, rAAV6-OGA preserved PI3K(p110α)-Akt signalling in diabetic mouse myocardium in vivo and prevented high glucose-induced impairments in mitochondrial respiration in human cardiomyocytes in vitro.
    CONCLUSION: Maladaptive protein O-GlcNAc modification is evident in human diabetic myocardium, and is a critical regulator of the diabetic heart phenotype. Selective targeting of cardiac protein O-GlcNAcylation to restore physiological O-GlcNAc balance may represent a novel therapeutic approach for diabetes-induced heart failure.
    TRANSLATIONAL PERSPECTIVE: There remains a lack of effective clinical management of diabetes-induced cardiac dysfunction, even via conventional intensive glucose-lowering approaches. Here we reveal that the modification of myocardial proteins by O-GlcNAc, a glucose-driven process, is not only increased in human diabetic myocardium, but correlates with reduced cardiac function in affected patients. Moreover, manipulation of the two regulatory enzymes of this process exert opposing influences on the heart, whereby increasing O-GlcNAc transferase (OGT) is sufficient to replicate the cardiac phenotype of diabetes (in the absence of this disease), while increasing O-GlcNAc-ase (OGA) rescues diabetes-induced impairments in both cardiac dysfunction and remodelling. Cardiac O-GlcNAcylation thus represents a novel therapeutic target for diabetes-induced heart failure.
    DOI:  https://doi.org/10.1093/cvr/cvab043
  11. Biochem Biophys Res Commun. 2021 Feb 06. pii: S0006-291X(21)00151-0. [Epub ahead of print]546 29-34
    Rosmarinic acid ameliorated cardiac dysfunction and mitochondrial injury in diabetic cardiomyopathy mice via activation of the SIRT1/PGC-1α pathway.
    Jiayu Diao, Hongmou Zhao, Penghua You, Hongjun You, Haoyu Wu, Xiling Shou, Gong Cheng.
      Mitochondrial injury plays an essential role in the pathogenesis of diabetic cardiomyopathy (DCM). Previous studies demonstrated that rosmarinic acid (RA) treatment prevented high glucose-induced mitochondrial injury in vitro. However, whether RA can ameliorate cardiac function by preventing mitochondrial injury in DCM is unknown. The SIRT1/PGC-1α pathway has emerged as an important regulator of metabolic control and other mitochondrial functions. The present study was undertaken to determine the effects of RA on mitochondrial and cardiac function in DCM as well as the involvement of the SIRT1/PGC-1α pathway. Our results revealed that RA improved cardiac systolic and diastolic function and prevented mitochondrial injury in DCM, as shown by the reduced blood glucose and lipid levels, increased mitochondrial membrane potential levels, improved adenosine triphosphate synthesis, and inhibited apoptosis (P < 0.05). Moreover, RA upregulated the expression of SIRT1 and PGC-1α in DCM mice and high glucose-treated H9c2 cardiomyocytes (P < 0.05). Further mechanistic studies in H9c2 cardiomyocytes revealed that suppression of SIRT1 by Sh-SIRT1 counteracted the effects of RA on high glucose-induced abnormal metabolism of glucose and lipids, oxidative stress and apoptosis (P < 0.05). Taken together, these data indicate that RA prevented mitochondrial injury and cardiac dysfunction in DCM mice, and the SIRT1/PGC-1α pathway mediated the protective effects of RA.
    Keywords:  Diabetic cardiomyopathy; Mitochondria; Rosmarinic acid; SIRT1
    DOI:  https://doi.org/10.1016/j.bbrc.2021.01.086
  12. Sci Rep. 2021 Feb 09. 11(1): 3426
    CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor.
    Masato Ishizuka, Mutsuo Harada, Seitaro Nomura, Toshiyuki Ko, Yuichi Ikeda, Jiaxi Guo, Satoshi Bujo, Haruka Yanagisawa-Murakami, Masahiro Satoh, Shintaro Yamada, Hidetoshi Kumagai, Yoshihiro Motozawa, Hironori Hara, Takayuki Fujiwara, Tatsuyuki Sato, Norifumi Takeda, Norihiko Takeda, Kinya Otsu, Hiroyuki Morita, Haruhiro Toko, Issei Komuro.
      Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
    DOI:  https://doi.org/10.1038/s41598-021-83022-5
  13. Am J Physiol Heart Circ Physiol. 2021 Feb 12.
    FoxO1 is required for physiological cardiac hypertrophy induced by exercise but not by constitutively active PI3K.
    Kate L Weeks, Yow Keat Tham, Suzan G Yildiz, Yonali Alexander, Daniel G Donner, Helen Kiriazis, Claudia A Harmawan, Amy T Hsu, Bianca C Bernardo, Aya Matsumoto, Ronald A DePinho, E Dale Abel, Elizabeth A Woodcock, Julie R McMullen.
      The insulin-like growth factor 1 receptor (IGF1R) and phosphoinositide 3-kinase p110a (PI3K) are critical regulators of exercise-induced physiological cardiac hypertrophy, and provide protection in experimental models of pathological remodeling and heart failure. Forkhead box class O1 (FoxO1) is a transcription factor which regulates cardiomyocyte hypertrophy downstream of IGF1R/PI3K activation in vitro, but its role in physiological hypertrophy in vivo was unknown. We generated cardiomyocyte-specific FoxO1 knockout (cKO) mice and assessed the phenotype under basal conditions and settings of physiological hypertrophy induced by 1) swim training, or 2) cardiac-specific transgenic expression of constitutively active PI3K (caPI3KTg+). Under basal conditions, male and female cKO mice displayed mild interstitial fibrosis compared with control (CON) littermates, but no other signs of cardiac pathology were present. In response to exercise training, female CON mice displayed an increase (~21%) in heart weight normalized to tibia length vs untrained mice. Exercise-induced hypertrophy was blunted in cKO mice. Exercise increased cardiac Akt phosphorylation and IGF1R expression, but was comparable between genotypes. However, differences in Foxo3a, Hsp70 and autophagy markers were identified in hearts of exercised cKO mice. Deletion of FoxO1 did not reduce cardiac hypertrophy in male or female caPI3KTg+ mice. Cardiac Akt and FoxO1 protein expression were significantly reduced in hearts of caPI3KTg+ mice, which may represent a negative feedback mechanism from chronic caPI3K, and negate any further effect of reducing FoxO1 in the cKO. In summary, FoxO1 contributes to exercise-induced hypertrophy. This has important implications when considering FoxO1 as a target for treating the diseased heart.
    Keywords:  Foxo1; cardiac hypertrophy; exercise; forkhead box protein; heart disease
    DOI:  https://doi.org/10.1152/ajpheart.00838.2020
  14. Ann Transl Med. 2021 Jan;9(2): 154
    The protective effects of the miR-129-5p/keap-1/Nrf2 axis on Ang II-induced cardiomyocyte hypertrophy.
    Huiming Ye, Guiyu Xu, Dexian Zhang, Rupeng Wang.
      Background: Cardiac hypertrophy is a common pathological process in many cardiac diseases, and persistent cardiac hypertrophy is the main cause of heart failure and sudden cardiogenic death. Thus, it is essential to elucidate the mechanism of cardiac hypertrophy to ensure better prevention and treatment.Methods: The Human cardiac myocytes (HCMs) were incubated with 100 nmol/L Ang II (Sigma) for 48 hours to induce the in vitro cardiomyocyte hypertrophy model. The [(3H])-leucine incorporation assay was used to evaluate cardiomyocytes hypertrophy. The activities of oxidative stress related enzymes superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA) and nitric oxide (NO) were detected using corresponding detection kits following standard protocol. Targeting relationship was verified through Bioinformatics analysis and luciferase reporter gene assay. The morphological change of cardiomyocyte was observed through immunofluorescence staining. Expressions of message ribonucleic acid (mRNA) and proteins were detected by quantitative real-time polymerase chain reaction and western blot, respectively.
    Results: In our study, the suppressed expression of micro ribonucleic acid (miRNA)-129-5p and the elevated expression of kelch-like ECH-associated protein 1 (keap-1) were found in the angiotensin II (Ang II)-induced cardiomyocyte hypertrophy model. MiR-129-5p effectively mimics suppressed Ang II-induced hypertrophic responses and oxidative stress. The results also showed that keap-1 was a target of miR-129-5p, and that the miR-129-5p inhibitor promoted cardiomyocyte hypertrophy and oxidative stress by elevating keap-1. Additionally, small interfering RNA (siRNA)-keap-1 activated the nuclear factor erythroid2-related factor 2 (Nrf2) pathway, while the miR-129-5p inhibitor inactivated the Nrf2 pathway by further elevating keap-1. The addition of the Nrf2 pathway activator NK-252 largely weakened the promoting effects of the miR-129-5p inhibitor on the progression of cardiomyocyte hypertrophy by suppressing oxidative stress.
    Conclusions: In general, the results indicate that the overexpression of miRNA-129-5p protects against cardiomyocyte hypertrophy by targeting keap-1 via the Nrf2 pathway.
    Keywords:  Cardio hypertrophy; Nrf2 pathway; keap-1; miR-129a-5p; oxidative stress
    DOI:  https://doi.org/10.21037/atm-20-8079
  15. In Vitro Cell Dev Biol Anim. 2021 Feb 12.
    Specific protein 1 inhibitor mithramycin A protects cardiomyocytes from myocardial infarction via interacting with PARP.
    Haihua Geng, Yamin Su, Rong Huang, Mengkang Fan, Xiaofei Li, Xiaochen Lu, Hongzhuan Sheng.
      Specific protein 1 (SP1) might act as a critical transcription regulator in myocardial infarction (MI), but little evidence about its function in regulating cardiac apoptosis, a major cause of MI development, has been revealed. This study tried to investigate the role of SP1 in MI and its interaction with poly-ADP-ribose polymerase (PARP)-1 by using SP1 inhibitor, mithramycin A (mithA). Primary mouse cardiomyocytes and commercial mouse cardiomyocytes were subjected to mithA treatment under hypoxia conditions, while cell viability, Nix promoter activity, and its expression were detected correspondingly. PARP overexpression and knockdown were conducted, respectively, in mithA-treated and SP1-overexpressing cells. Co-immunoprecipitation was used to verify the interaction between PARP and SP1. For in vivo experiments, mithA administration was performed after the injections of adenovirus for PARP overexpression, and then, MI introduction was carried out. Infarct size and lactate dehydrogenase level were measured to assess MI injury. SP1 inhibitor mithA attenuated hypoxia-induced decrease of cell viability and Nix transcriptional activation, which could be inhibited by PARP overexpression. Knockdown of PARP prevented SP1-induced transcription of Nix and cell viability change, and PARP showed direct interaction with SP1. Furthermore, mithA administration reduced MI injuries, while PARP overexpression could suppress the improvement. The cardioprotective role of SP1 inhibitor mithA was demonstrated here expanding the role of SP1 in MI development involving hypoxia-induced cardiac apoptosis. Moreover, PARP acted as a transcriptional coactivator in Nix transcription involving its interaction with SP1.
    Keywords:  Hypoxia-induced apoptosis; Myocardial infarction; Nix; PARP; SP1
    DOI:  https://doi.org/10.1007/s11626-021-00543-z
  16. Nat Commun. 2021 02 08. 12(1): 869
    The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction.
    Fan Jiang, Kunlun Yin, Kun Wu, Mingmin Zhang, Shiqiang Wang, Heping Cheng, Zhou Zhou, Bailong Xiao.
      The beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank-Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive. Here we show that the mechanically activated Piezo1 channel converts mechanical stretch of cardiomyocytes into Ca2+ and reactive oxygen species (ROS) signaling, which critically determines the mechanical activity of the heart. Either cardiac-specific knockout or overexpression of Piezo1 in mice results in defective Ca2+ and ROS signaling and the development of cardiomyopathy, demonstrating a homeostatic role of Piezo1. Piezo1 is pathologically upregulated in both mouse and human diseased hearts via an autonomic response of cardiomyocytes. Thus, Piezo1 serves as a key cardiac mechanotransducer for initiating mechano-chemo transduction and consequently maintaining normal heart function, and might represent a novel therapeutic target for treating human heart diseases.
    DOI:  https://doi.org/10.1038/s41467-021-21178-4
  17. Oxid Med Cell Longev. 2021 ;2021 1250858
    BGP-15 Protects against Heart Failure by Enhanced Mitochondrial Biogenesis and Decreased Fibrotic Remodelling in Spontaneously Hypertensive Rats.
    Orsolya Horvath, Katalin Ordog, Kitti Bruszt, Laszlo Deres, Ferenc Gallyas, Balazs Sumegi, Kalman Toth, Robert Halmosi.
      Heart failure (HF) is a complex clinical syndrome with poor clinical outcomes despite the growing number of therapeutic approaches. It is characterized by interstitial fibrosis, cardiomyocyte hypertrophy, activation of various intracellular signalling pathways, and damage of the mitochondrial network. Mitochondria are responsible for supplying the energy demand of cardiomyocytes; therefore, the damage of the mitochondrial network causes cellular dysfunction and finally leads to cell death. BGP-15, a hydroxylamine derivative, is an insulin-sensitizer molecule and has a wide range of cytoprotective effects in animal as well as in human studies. Our recent work was aimed at examining the effects of BGP-15 in a chronic hypertension-induced heart failure model. 15-month-old male SHRs were used in our experiment. The SHR-Baseline group represented the starting point (n = 7). Animals received BGP-15 (SHR-B, n = 7) or placebo (SHR-C, n = 7) for 18 weeks. WKY rats were used as age-matched normotensive controls (n = 7). The heart function was monitored by echocardiography. Histological preparations were made from cardiac tissue. The levels of signalling proteins were determined by Western blot. At the end of the study, systolic and diastolic cardiac function was preserved in the BGP-treated animals. BGP-15 decreased the interstitial collagen deposition via decreasing the activity of TGFβ/Smad signalling factors and prevented the cardiomyocyte hypertrophy in hypertensive animals. BGP-15 enhanced the prosurvival signalling pathways (Akt/Gsk3β). The treatment increased the activity of MKP1 and decreased the activity of p38 and JNK signalling routes. The mitochondrial mass of cardiomyocytes was also increased in BGP-15-treated SHR animals due to the activation of mitochondrial biogenesis. The mitigation of remodelling processes and the preserved systolic cardiac function in hypertension-induced heart failure can be a result-at least partly-of the enhanced mitochondrial biogenesis caused by BGP-15.
    DOI:  https://doi.org/10.1155/2021/1250858
  18. Nucleic Acids Res. 2021 Feb 09. pii: gkab055. [Epub ahead of print]
    Novel roles of an intragenic G-quadruplex in controlling microRNA expression and cardiac function.
    Min Zhu, Juan Gao, Xian-Juan Lin, Yun-Yun Gong, Yan-Chao Qi, Yuan-Liang Ma, Yuan-Xiu Song, Wei Tan, Fang-Yuan Li, Min Ye, Jun Gong, Qing-Hua Cui, Zeng-Hui Huang, You-Yi Zhang, Xiu-Jie Wang, Feng Lan, Shi-Qiang Wang, Gu Yuan, Yue Feng, Ming Xu.
      Simultaneous dysregulation of multiple microRNAs (miRs) affects various pathological pathways related to cardiac failure. In addition to being potential cardiac disease-specific markers, miR-23b/27b/24-1 were reported to be responsible for conferring cardiac pathophysiological processes. In this study, we identified a conserved guanine-rich RNA motif within the miR-23b/27b/24-1 cluster that can form an RNA G-quadruplex (rG4) in vitro and in cells. Disruption of this intragenic rG4 significantly increased the production of all three miRs. Conversely, a G4-binding ligand tetrandrine (TET) stabilized the rG4 and suppressed miRs production in human and rodent cardiomyocytes. Our further study showed that the rG4 prevented Drosha-DGCR8 binding and processing of the pri-miR, suppressing the biogenesis of all three miRs. Moreover, CRISPR/Cas9-mediated G4 deletion in the rat genome aberrantly elevated all three miRs in the heart in vivo, leading to cardiac contractile dysfunction. Importantly, loss of the G4 resulted in reduced targets for the aforementioned miRs critical for normal heart function and defects in the L-type Ca2+ channel-ryanodine receptor (LCC-RyR) coupling in cardiomyocytes. Our results reveal a novel mechanism for G4-dependent regulation of miR biogenesis, which is essential for maintaining normal heart function.
    DOI:  https://doi.org/10.1093/nar/gkab055
  19. J Cell Mol Med. 2021 Feb 09.
    Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress.
    Linmao Lyu, Jiazheng Chen, Wei Wang, Tao Yan, Jiamao Lin, Hongmei Gao, Hui Li, Ruijuan Lv, Feng Xu, Lijun Fang, Yuguo Chen.
      Long-term poorly controlled myocardial hypertrophy often leads to heart failure and sudden death. Activation of ras-related C3 botulinum toxin substrate 1 (RAC1) by angiotensin II (Ang II) plays a pivotal role in myocardial hypertrophy. Previous studies have demonstrated that scoparone (SCO) has beneficial effects on hypertension and extracellular matrix remodelling. However, the function of SCO on Ang II-mediated myocardial hypertrophy remains unknown. In our study, a mouse model of myocardial hypertrophy was established by Ang II infusion (2 mg/kg/day) for 4 weeks, and SCO (60 mg/kg bodyweight) was administered by gavage daily. In vitro experiments were also performed. Our results showed that SCO could alleviate Ang II infusion-induced cardiac hypertrophy and fibrosis in mice. In vitro, SCO treatment blocks Ang II-induced cardiomyocyte hypertrophy, cardiac fibroblast collagen synthesis and differentiation to myofibroblasts. Meanwhile, we found that SCO treatment blocked Ang II-induced oxidative stress in cardiomyocytes and cardiac fibroblasts by inhibiting RAC1-GTP and total RAC1 in vivo and in vitro. Furthermore, reactive oxygen species (ROS) burst by overexpression of RAC1 completely abolished SCO-mediated protection in cardiomyocytes and cardiac fibroblasts in vitro. In conclusion, SCO, an antioxidant, may attenuate Ang II-induced myocardial hypertrophy by suppressing of RAC1 mediated oxidative stress.
    Keywords:  angiotensin II; fibrosis; hypertrophy; oxidative stress; scoparone
    DOI:  https://doi.org/10.1111/jcmm.16304
  20. Biomed Pharmacother. 2021 Feb 05. pii: S0753-3322(21)00103-7. [Epub ahead of print]137 111318
    Qingda granule attenuates cardiac fibrosis via suppression of the TGF-β1/Smad2/3 signaling pathway in vitro and in vivo.
    Xiaoping Chen, Linzi Long, Ying Cheng, Jianfeng Chu, Zhiqing Shen, Liya Liu, Jiapeng Li, Qiurong Xie, Huixin Liu, Meizhu Wu, Youqin Chen, Jun Peng, Aling Shen.
      Cardiac fibrosis plays an important role in hypertension-related contractile dysfunction and heart failure. Qingda granule (QDG), derived from the Qingxuan Jiangya decoction, has been used clinically for more than 60 years to treat hypertension. However, the effect of QDG on hypertensive cardiac fibrosis remains largely unknown. The objective of this study was to investigate the effect of QDG on cardiac fibrosis and explore the underlying mechanism in vivo and in vitro. For in vivo experiments, 30 male spontaneously hypertensive rats were randomly divided into groups that received no QDG or one of three doses (0.45, 0.9 or 1.8 g/kg/day). Positive-control animals received valsartan (VAL, 7.2 mg/kg/day). Treatments were administered by gavage for 10 weeks. All three doses of QDG and VAL led to significantly lower blood pressure than in SHR animals. Besides, all three doses of QDG and VAL attenuated pathological changes in SHR animals. However, only intermediate, high concentrations of QDG and VAL led to significantly lower left ventricle ejection fraction and left ventricle fractional shortening than in SHR animals. Therefore, the minimum and effective QDG dose (intermediate concentration of QDG) was selected for subsequent animal experiments in this study. Our results showed that intermediate concentration of QDG also significantly mitigated the increases in levels of α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), collagen III, transforming growth factor-β1 (TGF-β1) and in the ratio of phospho-Smad2/3 to total Smad2/3 protein in cardiac tissue, based on immunohistochemistry, Western blotting, and Masson staining. For in vitro experiments, primary cardiac fibroblasts were stimulated with 100 nM angiotensin II in the presence or absence of QDG. And we tested different concentrations of QDG (3.125, 6.25, 12.5, 25, 50 μg/mL) in the cell viability experiment. Our results showed that 3.125, 6.25 and 12.5 μg/mL of QDG treatment for 24 h didn't affect the cell viability of cardiac fibroblasts. Consistently, QDG at 6.25 or 12.5 μg/mL significantly reduced cell viability and down-regulated α-SMA in primary cardiac fibroblasts were stimulated with 100 nM angiotensin II. Therefore, QDG at 12.5 μg/mL was chosen for the following cell experiment. Our results showed that QDG at 12.5 μg/mL alleviated the increase of PCNA, collagen Ⅲ, TGF-β1 expression, and the ratio of phospho-Smad2/3 to total Smad2/3 protein. Our studies in vitro and in vivo suggest that QDG reduces blood pressure and cardiac fibrosis as well as protecting cardiac function, and that it exerts these effects in part by suppressing TGF-β1/Smad2/3 signaling.
    Keywords:  Cardiac fibrosis; Hypertension; Qingda granule; TGF-β1/Smad2/3
    DOI:  https://doi.org/10.1016/j.biopha.2021.111318
  21. J Mol Cell Cardiol. 2021 Feb 04. pii: S0022-2828(21)00020-1. [Epub ahead of print]154 21-31
    Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload.
    Yusuke Igaki, Masaya Tanno, Tatsuya Sato, Hidemichi Kouzu, Toshifumi Ogawa, Arata Osanami, Toshiyuki Yano, Atsushi Kuno, Takayuki Miki, Takashi Nakamura, Tetsuji Miura.
      BACKGROUND: We previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats.METHODS AND RESULTS: Pressure-volume loop analysis revealed that pressure overloading by phenylephrine infusion induced severer left ventricular diastolic dysfunction (tau: 14.7 ± 0.8 vs 12.5 ± 0.7 msec, left ventricular end-diastolic pressure: 18.3 ± 1.5 vs 12.2 ± 1.3 mmHg, p < 0.05) and ventricular-arterial uncoupling in OLETF than in LETO, non-diabetic rats, though the baseline parameters were comparable in the two groups. While the pressure overload did not affect AMPD activity, it increased XOR activity both in OLETF and LETO, with OLETF showing significantly higher XOR activity than that in LETO (347.2 ± 17.9 vs 243.2 ± 6.1 μg/min/mg). Under the condition of pressure overload, myocardial ATP level was lower, and levels of xanthine and uric acid were higher in OLETF than in LETO. Addition of exogenous inosine, a product of AMP deamination, to the heart homogenates augmented XOR activity. OLETF showed 68% higher tissue ROS levels and 47% reduction in mitochondrial state 3 respiration compared with those in LETO. Overexpression of AMPD3 in H9c2 cells elevated levels of hypoxanthine and ROS and reduced the level of ATP. Inhibition of XOR suppressed the production of tissue ROS and mitochondrial dysfunction and improved ventricular function under the condition of pressure overload in OLETF.
    CONCLUSIONS: The results suggest that increases in the activity of XOR and the formation of XOR substrates by upregulated AMPD contribute to ROS-mediated diastolic ventricular dysfunction at the time of increased cardiac workload in diabetic hearts.
    Keywords:  AMP deaminase; Diabetic cardiomyopathy; Heart failure; Mitochondria; Xanthine oxidoreductase
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.01.002
  22. Eur Rev Med Pharmacol Sci. 2021 Jan;pii: 24646. [Epub ahead of print]25(2): 812-819
    Effects of PPARγ agonist pioglitazone on cardiac fibrosis in diabetic mice by regulating PTEN/AKT/FAK pathway.
    X-D Zhang, G-X Sun, J-J Guo, C-C Hu, R-C Sun, H-C Yu.
      OBJECTIVE: The aim of this study was to explore the role of pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, in cardiac fibrosis of diabetic mice.MATERIALS AND METHODS: A total of 60 adult male C57/B6 mice were divided into 3 groups using a random number table, namely, control group (Sham group, n=20), diabetic cardiomyopathy group (DCM group, n=20), DCM + PIO group (n=20). Streptozocin (STZ) was injected into mice at a dose of 125 mg/Kg to induce the model of diabetes in vivo. After successful induction, mice in DCM + PIO group were intragastrically given PIO at 10 mg/kg/d once a day for 6 weeks. Meanwhile, those in Sham group and DCM group were given the same volume of normal saline. After 6 weeks, ejection fraction % (EF%), fraction shortening % (FS%) and heart rate of mice in each group were examined via echocardiography. Picrosirius red (PSR) staining assay was conducted to detect collagen deposition in myocardial tissues of mice in each group. The protein expression level of PPARγ in mouse myocardial tissues in each group was measured through Western blotting and immunohistochemical staining assays. Hematoxylin-eosin (H&E) staining assay was carried out to evaluate the myocardial hypertrophy of mice in each group. The protein expression level of transforming growth factor-β (TGF-β) in mouse myocardial tissues in each group was measured through immunohistochemical staining assay. In addition, Western blotting was employed to detect the expression of proteins related to the phosphate and tension homology deleted on chromsome ten (PTEN)/protein kinase B (AKT)/focal adhesion kinase (FAK) signaling pathway in myocardial tissues of mice in each group.
    RESULTS: The messenger ribonucleic acid (mRNA) and protein expression levels of PPARγ in mouse myocardial tissues were significantly lower in DCM group than those in Sham group (p<0.05). PPARγ agonist PIO could significantly increase the protein expression of PPARγ in myocardial tissues of DCM mice. The results of cardiac Doppler ultrasound revealed that PIO significantly upregulated EF% and FS% in DCM mice (p<0.05). Besides, PIO remarkably reduced collagen deposition and TGF-β protein expression in myocardial tissues in DCM mice (p<0.05). H&E staining results showed that PIO notably attenuated myocardial hypertrophy in DCM mice (p<0.05). Furthermore, it was discovered that PIO markedly elevated PTEN protein in myocardial tissues of DCM mice and inhibited the phosphorylation of AKT and FAK proteins (p<0.05).
    CONCLUSIONS: The protective effect of PIO against cardiac fibrosis in diabetic mice may be related to its regulation on the PTEN/AKT/FAK signaling pathway. Our findings suggest that PIO is expected to become a targeted drug for the treatment of DCM in clinical practice.
    DOI:  https://doi.org/10.26355/eurrev_202101_24646
  23. Biomed Res Int. 2021 ;2021 8881843
    Forskolin Protected against Streptozotocin-Induced Diabetic Cardiomyopathy via Inhibition of Oxidative Stress and Cardiac Fibrosis in Mice.
    Xu Zhang, Pei-Xiong Ke, Xun Yuan, Gui-Ping Zhang, Wen-Liang Chen, Gen-Shui Zhang.
      Background: Diabetic cardiomyopathy is one of the cardiac complications in diabetes patients, eventually resulting in heart failure and increasing morbidity and mortality. Oxidative stress is a critical pathological feature in diabetic hearts, contributing to the development of DCM. Forskolin (FSK) was shown to reduce oxidative stress. This study was aimed at investigating the effects of FSK on diabetic hearts and the relevant molecular mechanisms.Methods: Streptozotocin- (STZ-) induced diabetes in mice was treated with FSK through intraperitoneal injection. Cardiac functions were evaluated by echocardiography. Hematoxylin-eosin and Masson trichrome staining was employed to determine heart morphological changes and cardiac fibrosis, respectively. Cardiac fibrosis-related markers were detected by western blot. Superoxide dismutase activity, reduced/oxidized glutathione ratio, and malondialdehyde concentration in left ventricles were determined using respective commercial kits.
    Results: Abnormal cardiac diastolic dysfunction and cardiac fibrosis were observed in diabetic hearts. FSK treatment significantly improved the cardiac diastolic function and attenuated the abnormal morphological change in diabetic hearts. Moreover, FSK treatment in diabetic mice decreased the expression of fibronectin, collagen I, TGF-β, and α-SMA and reduced myocardial fibrosis. Furthermore, we observed that FSK significantly blocked oxidative stress in diabetic hearts.
    Conclusions: Our study demonstrates that FSK protects against the development of DCM in STZ-induced diabetes in mice. Our study suggests that FSK might be a potential target for drug development in treating DCM.
    DOI:  https://doi.org/10.1155/2021/8881843
  24. Int J Mol Sci. 2021 Jan 25. pii: 1177. [Epub ahead of print]22(3):
    Empagliflozin and Liraglutide Differentially Modulate Cardiac Metabolism in Diabetic Cardiomyopathy in Rats.
    Nguyen Ngoc Trang, Cheng-Chih Chung, Ting-Wei Lee, Wan-Li Cheng, Yu-Hsun Kao, Shih-Yu Huang, Ting-I Lee, Yi-Jen Chen.
      Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are antihyperglycemic agents with cardioprotective properties against diabetic cardiomyopathy (DCM). However, the distinctive mechanisms underlying GLP-1RAs and SGLT2is in DCM are not fully elucidated. The purpose of this study was to investigate the impacts of GLP1RAs and/or SGLT2is on myocardial energy metabolism, cardiac function, and apoptosis signaling in DCM. Biochemistry and echocardiograms were studied before and after treatment with empagliflozin (10 mg/kg/day, oral gavage), and/or liraglutide (200 μg/kg every 12 h, subcutaneously) for 4 weeks in male Wistar rats with streptozotocin (65 mg/kg intraperitoneally)-induced diabetes. Cardiac fibrosis, apoptosis, and protein expression of metabolic and inflammatory signaling molecules were evaluated by histopathology and Western blotting in ventricular cardiomyocytes of different groups. Empagliflozin and liraglutide normalized myocardial dysfunction in diabetic rats. Upregulation of phosphorylated-acetyl coenzyme A carboxylase, carnitine palmitoyltransferase 1β, cluster of differentiation 36, and peroxisome proliferator-activated receptor-gamma coactivator, and downregulation of glucose transporter 4, the ratio of phosphorylated adenosine monophosphate-activated protein kinase α2 to adenosine monophosphate-activated protein kinase α2, and the ratio of phosphorylated protein kinase B to protein kinase B in diabetic cardiomyocytes were restored by treatment with empagliflozin or liraglutide. Nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3, interleukin-1β, tumor necrosis factor-α, and cleaved caspase-1 were significantly downregulated in empagliflozin-treated and liraglutide-treated diabetic rats. Both empagliflozin-treated and liraglutide-treated diabetic rats exhibited attenuated myocardial fibrosis and apoptosis. Empagliflozin modulated fatty acid and glucose metabolism, while liraglutide regulated inflammation and apoptosis in DCM. The better effects of combined treatment with GLP-1RAs and SGLT2is may lead to a potential strategy targeting DCM.
    Keywords:  diabetic cardiomyopathy; empagliflozin; fatty acid and glucose metabolism; glucagon-like peptide 1 receptor agonists; inflammation; liraglutide; sodium-glucose cotransporter-2 inhibitors
    DOI:  https://doi.org/10.3390/ijms22031177
  25. Cell Biol Int. 2021 Feb 08.
    GPR39 promotes cardiac hypertrophy by regulating the AMPK-mTOR pathway and protein synthesis.
    Hongjuan Liao, Weinian Gao, Jie Ma, Hongyuan Xue, Yi Wang, Dai Huang, Fang Yan, Yuquan Ye.
      Hypertrophic growth of the cardiomyocytes is one of the core mechanisms underlying cardiac hypertrophy. However, the mechanism underlying cardiac hypertrophy remains not fully understood. Here we provided evidence that G protein-coupled receptor 39 (GPR39) promotes cardiac hypertrophy via inhibiting AMPK signaling. GRP39 expression is overexpressed in hypertrophic hearts of humans and transverse aortic constriction (TAC)-induced cardiac hypertrophy in mice. In neonatal cardiomyocytes, adenovirus-mediated overexpression of GPR39 promoted angiotensin II-induced cardiac hypertrophy while GPR39 knockdown repressed hypertrophic response. Adeno-associated virus 9 (AAV9)-mediated knockdown of GPR39 suppressed TAC-induced decline in fraction shortening and ejection fraction, increase in heart weight and cardiomyocyte size, as well as overexpression of hypertrophic fetal genes. Mechanism study demonstrated that GPR39 repressed the activation of AMPK to activate the mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase beta-1 (S6K1), subsequently promoted de novo protein synthesis. Inhibition of mTOR with rapamycin blocked the effects of GPR39 overexpression on protein synthesis and repressed cardiac hypertrophy. Collectively, our findings demonstrated that GPR39 promoted cardiac hypertrophy via regulating the AMPK-mTOR-S6K1 signaling pathway, and GRP39 can be targeted for the treatment of cardiac hypertrophy. This article is protected by copyright. All rights reserved.
    Keywords:  AMPK; Cardiac hypertrophy; GPR39; S6K1; mTOR; protein synthesis; rapamycin
    DOI:  https://doi.org/10.1002/cbin.11566
  26. Int J Mol Sci. 2021 Feb 05. pii: 1600. [Epub ahead of print]22(4):
    Nuclear Receptor Nur77 Controls Cardiac Fibrosis through Distinct Actions on Fibroblasts and Cardiomyocytes.
    Lejla Medzikovic, Hylja Heese, Pieter B van Loenen, Cindy P A A van Roomen, Ingeborg B Hooijkaas, Vincent M Christoffels, Esther E Creemers, Carlie J M de Vries, Vivian de Waard.
      Fibrosis is a hallmark of adverse cardiac remodeling, which promotes heart failure, but it is also an essential repair mechanism to prevent cardiac rupture, signifying the importance of appropriate regulation of this process. In the remodeling heart, cardiac fibroblasts (CFs) differentiate into myofibroblasts (MyoFB), which are the key mediators of the fibrotic response. Additionally, cardiomyocytes are involved by providing pro-fibrotic cues. Nuclear receptor Nur77 is known to reduce cardiac hypertrophy and associated fibrosis; however, the exact function of Nur77 in the fibrotic response is yet unknown. Here, we show that Nur77-deficient mice exhibit severe myocardial wall thinning, rupture and reduced collagen fiber density after myocardial infarction and chronic isoproterenol (ISO) infusion. Upon Nur77 knockdown in cultured rat CFs, expression of MyoFB markers and extracellular matrix proteins is reduced after stimulation with ISO or transforming growth factor-β (TGF-β). Accordingly, Nur77-depleted CFs produce less collagen and exhibit diminished proliferation and wound closure capacity. Interestingly, Nur77 knockdown in neonatal rat cardiomyocytes results in increased paracrine induction of MyoFB differentiation, which was blocked by TGF-β receptor antagonism. Taken together, Nur77-mediated regulation involves CF-intrinsic promotion of CF-to-MyoFB transition and inhibition of cardiomyocyte-driven paracrine TGF-β-mediated MyoFB differentiation. As such, Nur77 provides distinct, cell-specific regulation of cardiac fibrosis.
    Keywords:  cardiac; cardiomyocyte; fibroblast; fibrosis; myofibroblast; nuclear receptor; transforming growth factor β
    DOI:  https://doi.org/10.3390/ijms22041600
  27. Pharmacol Res. 2021 Feb 03. pii: S1043-6618(21)00049-9. [Epub ahead of print] 105466
    Ferroptosis and its emerging roles in cardiovascular diseases.
    Ning Li, Wenyang Jiang, Wei Wang, Rui Xiong, Xiaojing Wu, Qing Geng.
      Ferroptosis is a new form of regulated cell death (RCD) driven by iron-dependent lipid peroxidation, which is morphologically and mechanistically distinct from other forms of RCD including apoptosis, autophagic cell death, pyroptosis and necroptosis. Recently, ferroptosis has been found to participate in the development of various cardiovascular diseases (CVDs) including doxorubicin-induced cardiotoxicity, ischemia/reperfusion-induced cardiomyopathy, heart failure, aortic dissection and stroke. Cardiovascular homeostasis is indulged in delicate equilibrium of assorted cell types composing the heart or vessels, and how ferroptosis contributes to the pathophysiological responses in CVD progression is unclear. Herein, we reviewed recent discoveries on the basis of ferroptosis and its involvement in CVD pathogenesis, together with related therapeutic potentials, aiming to provide insights on fundamental mechanisms of ferroptosis and implications in CVDs and associated disorders.
    Keywords:  cardiovascular disease; ferroptosis; iron; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.phrs.2021.105466
  28. Front Pharmacol. 2020 ;11 586498
    Paeonol Protects Against Myocardial Ischemia/Reperfusion-Induced Injury by Mediating Apoptosis and Autophagy Crosstalk.
    Chin-Feng Tsai, Hsing-Hui Su, Ke-Min Chen, Jiuan-Miaw Liao, Yi-Ting Yao, Yi-Hung Chen, Meilin Wang, Ya-Chun Chu, Yi-Hsin Wang, Shiang-Suo Huang.
      Many studies have shown that crosstalk exists between apoptosis and autophagy, despite differences in mechanisms between these processes. Paeonol, a major phenolic compound isolated from Moutan Cortex Radicis, the root bark of Paeonia × suffruticosa Andrews (Paeoniaceae), is widely used in traditional Chinese medicine as an antipyretic, analgesic and anti-inflammatory agent. In this study, we investigated the detailed molecular mechanisms of the crosstalk between apoptosis and autophagy underlying the cardioprotective effects of paeonol in rats subjected to myocardial ischemia/reperfusion (I/R) injury. Myocardial I/R injury was induced by occlusion of the left anterior descending coronary artery (LAD) for 1 h followed by 3 h of reperfusion. Paeonol was intravenously administered 15 min before LAD ligation. We found that paeonol significantly improved cardiac function after myocardial I/R injury and significantly decreased myocardial I/R-induced arrhythmia and mortality. Paeonol also significantly decreased myocardial infarction and plasma LDH activity and Troponin-I levels in carotid blood after I/R. Compared with vehicle treatment, paeonol significantly upregulated Bcl-2 protein expression and significantly downregulated the cleaved forms of caspase-8, caspase-9, caspase-3 and PARP protein expression in the I/R injured myocardium. Myocardial I/R-induced autophagy, including the increase of Beclin-1, p62, LC3-I, and LC3-II protein expression in the myocardium was significantly reversed by paeonol treatment. Paeonol also significantly increased the Bcl-2/Bax and Bcl-2/Beclin-1 ratios in the myocardium after I/R injury. The cardioprotective role of paeonol during I/R injury may be due to its mediation of crosstalk between apoptotic and autophagic signaling pathways, which inhibits apoptosis and autophagic cell death.
    Keywords:  apoptosis; autophagy; crosstalk; myocardial ischemia/reperfusion injury; paeonol
    DOI:  https://doi.org/10.3389/fphar.2020.586498
  29. J Mol Histol. 2021 Feb 09.
    LGR4 silence aggravates ischemic injury by modulating mitochondrial function and oxidative stress via ERK signaling pathway in H9c2 cells.
    Tao Chen, Xiangrui Qiao, Lele Cheng, Mengping Liu, Yangyang Deng, Xiaozhen Zhuo.
      It is reported that LGR4 (leucine-rich repeat domain containing G protein-coupled receptor 4) plays a crucial role in the physiological function of many organs. However, few data are available on the function and mechanism of LGR4 in myocardial ischemia-reperfusion (I/R) injury. The aim of this study was to explore the function and mechanism of LGR4 in I/R injury. We incubated H9c2 cells in simulating ischemia buffer and then re-incubated them in normal culture medium to establish a model of I/R injury in vitro. The expression of LGR4 was evaluated by RT-PCR and western blot. Besides, the cell apoptosis was evaluated by flow cytometric analysis and the content of ROS, SOD, MDA, LDH, CK, ATP, cyt c were detected by special commercial kits. The expression of mitochondrial function-related proteins were detected by western blot. Then, the roles of ERK signaling pathway was determined with TBHQ (ERK activator) treatment. Our data have demonstrated that I/R boosted the expression of LGR4 in H9c2 cells. Knockdown of LGR4 increased the apoptosis rate of H9c2 cells and led to excessed oxidant stress and impaired mitochondrial function by increasing the levels of ROS, MDA, LDH, CK and cyt c and inhibiting SOD activity, ATP production. In addition, LGR4 silence inhibited the activation of ERK pathway. And TBHQ partially reversed the effects of LGR4 knockdown on H9c2 cells. To conclude, our study indicated that LGR4 regulated mitochondrial dysfunction and oxidative stress by ERK signaling pathways, which provides a potential cardiac protective target against I/R.
    Keywords:  ERK signaling pathway; Ischemic myocardial injury; LGR4; Mitochondrial function; Oxidative stress
    DOI:  https://doi.org/10.1007/s10735-021-09957-1
  30. Biochem Biophys Rep. 2021 Mar;25 100926
    Loss of endothelial cell-specific autophagy-related protein 7 exacerbates doxorubicin-induced cardiotoxicity.
    Albert Z Luu, Vincent Z Luu, Biswajit Chowdhury, Andrew Kosmopoulos, Yi Pan, Mohammed Al-Omran, Adrian Quan, Hwee Teoh, David A Hess, Subodh Verma.
      Doxorubicin (DOX) is an effective, broad-spectrum antineoplastic agent with serious cardiotoxic side effects, which may lead to the development of heart failure. Current strategies to diagnose, prevent, and treat DOX-induced cardiotoxicity (DIC) are inadequate. Recent evidence has linked the dysregulation and destruction of the vascular endothelium to the development of DIC. Autophagy is a conserved pro-survival mechanism that recycles and removes damaged sub-cellular components. Autophagy-related protein 7 (ATG7) catalyzes autophagosome formation, a critical step in autophagy. In this study, we used endothelial cell-specific Atg7 knockout (EC-Atg7 -/- ) mice to characterize the role of endothelial cell-specific autophagy in DIC. DOX-treated EC-Atg7 -/- mice showed reduced survival and a greater decline in cardiac function compared to wild-type controls. Histological assessments revealed increased cardiac fibrosis in DOX-treated EC-Atg7 -/- mice. Furthermore, DOX-treated EC-Atg7 -/- mice had elevated serum levels of creatine kinase-myocardial band, a biomarker for cardiac damage. Thus, the lack of EC-specific autophagy exacerbated DIC. Future studies on the relationship between EC-specific autophagy and DIC could establish the importance of endothelium protection in preventing DIC.
    Keywords:  Autophagy; Cardiomyopathy; Doxorubicin; Endothelium; Heart failure
    DOI:  https://doi.org/10.1016/j.bbrep.2021.100926
  31. Cell Death Discov. 2021 Feb 10. 7(1): 31
    IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury.
    Guixi Mo, Xin Liu, Yiyue Zhong, Jian Mo, Zhiyi Li, Daheng Li, Liangqing Zhang, Yijun Liu.
      Intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1) releases Ca2+ from endoplasmic reticulum. The disturbance of IP3R1 is related to several neurodegenerative diseases. This study investigated the mechanism of IP3R1 in myocardial ischemia/reperfusion (MI/R). After MI/R modeling, IP3R1 expression was silenced in myocardium of MI/R rats to explore its role in the concentration of myocardial enzymes, infarct area, Ca2+ level, NLRP3/Caspase-1, and pyroptosis markers and inflammatory factors. The adult rat cardiomyocytes were isolated and cultured to establish hypoxia/reperfusion (H/R) cell model. The expression of IP3R1 was downregulated or ERP44 was overexpressed in H/R-induced cells. Nifedipine D6 was added to H/R-induced cells to block Ca2+ channel or Nigericin was added to activate NLRP3. IP3R1 was highly expressed in myocardium of MI/R rats, and silencing IP3R1 alleviated MI/R injury, reduced Ca2+ overload, inflammation and pyroptosis in MI/R rats, and H/R-induced cells. The binding of ERP44 to IP3R1 inhibited Ca2+ overload, alleviated cardiomyocyte inflammation, and pyroptosis. The increase of intracellular Ca2+ level caused H/R-induced cardiomyocyte pyroptosis through the NLRP3/Caspase-1 pathway. Activation of NLRP3 pathway reversed the protection of IP3R1 inhibition/ERP44 overexpression/Nifedipine D6 on H/R-induced cells. Overall, ERP44 binding to IP3R1 inhibits Ca2+ overload, thus alleviating pyroptosis and MI/R injury.
    DOI:  https://doi.org/10.1038/s41420-021-00404-4
  32. Circ Res. 2021 Feb 08.
    LncRNA ZNF593-AS Alleviates Contractile Dysfunction in Dilated Cardiomyopathy.
    Jiahui Fan, Huaping Li, Rong Xie, Xudong Zhang, Xiang Nie, Xiaolu Shi, Jiabing Zhan, Zhongwei Yin, Yanru Zhao, Beibei Dai, Shuai Yuan, Zheng Wen, Chen Chen, Dao Wen Wang.
      Rationale: Previously, we identified the human cardiac long non-coding RNAs (lncRNAs) profile in dilated cardiomyopathy (DCM) patients, among which ZNF593-AS, also named as RP11-96L14.7 and ENST00000448923.2, showed good conservation among species. Objective: We aim to elucidate the mechanism underlying lncRNA in DCM and DCM that lead to heart failure, which might provide new insights into the mechanisms of DCM and possible treatment strategies in the future. Methods and Results: lncRNA expression was measured by real-time PCR and in situ hybridization assays. Coding potential was verified by bioinformatic and biologic assays. Recombinant adeno-associated virus with cardiac specific promoter was used to deliver lncRNA in vivo, while cardiac structure and functions were assessed by echocardiography and catheter. Sarcomere shortening, calcium imaging, gene expression profiling, and pull-down assays were performed to investigate the underlying mechanisms. ZNF593-AS, which mainly localized in the cytoplasm of cardiomyocytes, was robustly decreased in the failing heart of DCM patients, as well as in phenylephrine-treated human cardiomyocytes. Overexpression of mmu-ZNF593-AS significantly improved transverse aortic constriction (TAC)-induced cardiac dysfunction in mice. Moreover, ZNF593-AS overexpression restored the aberrant Ca2+ handling and contractility of cardiomyocytes from TAC-treated mice. Further, we found that ZNF593-AS acted as a guide RNA scaffold and recruited HNRNPC to ryanodine receptor type 2 (RYR2) mRNA, which in turn facilitated RYR2 mRNA stability, contributed to the improvement of cardiac Ca2+ handling and contractile function in DCM. Conclusions: Our findings suggested that lncRNA-based therapeutics may protect against DCM.
    Keywords:  HNRNPC; RYR2; ZNF593-AS
    DOI:  https://doi.org/10.1161/CIRCRESAHA.120.318437
  33. Pflugers Arch. 2021 Feb 13.
    Development of an AAV9-RNAi-mediated silencing strategy to abrogate TRPM4 expression in the adult heart.
    Rebekka Medert, Andreas Jungmann, Staffan Hildebrand, Martin Busch, Dirk Grimm, Veit Flockerzi, Oliver J Müller, Patrick Most, Dagmar Schumacher, Marc Freichel.
      The cation channel transient receptor potential melastatin 4 (TRPM4) is a calcium-activated non-selective cation channel and acts in cardiomyocytes as a negative modulator of the L-type Ca2+ influx. Global deletion of TRPM4 in the mouse led to increased cardiac contractility under β-adrenergic stimulation. Consequently, cardiomyocyte-specific inactivation of the TRPM4 function appears to be a promising strategy to improve cardiac contractility in heart failure patients. The aim of this study was to develop a gene therapy approach in mice that specifically silences the expression of TRPM4 in cardiomyocytes. First, short hairpin RNAmiR30 (shRNAmiR30) sequences against the TRPM4 mRNA were screened in vitro using lentiviral transduction for a stable expression of the shRNA cassettes. Western blot analysis identified three efficient shRNAmiR30 sequences out of six, which reduced the endogenous TRPM4 protein level by up to 90 ± 6%. Subsequently, the most efficient shRNAmiR30 sequences were delivered into cardiomyocytes of adult mice using adeno-associated virus serotype 9 (AAV9)-mediated gene transfer. Initially, the AAV9 vector particles were administered via the lateral tail vein, which resulted in a downregulation of TRPM4 by 46 ± 2%. Next, various optimization steps were carried out to improve knockdown efficiency in vivo. First, the design of the expression cassette was streamlined for integration in a self-complementary AAV vector backbone for a faster expression. Compared to the application via the lateral tail vein, intravenous application via the retro-orbital sinus has the advantage that the vector solution reaches the heart directly and in a high concentration, and eventually a TRPM4 knockdown efficiency of 90 ± 7% in the heart was accomplished by this approach. By optimization of the shRNAmiR30 constructs and expression cassette as well as the route of AAV9 vector application, a 90% reduction of TRPM4 expression was achieved in the adult mouse heart. In the future, AAV9-RNAi-mediated inactivation of TRPM4 could be a promising strategy to increase cardiac contractility in preclinical animal models of acute and chronic forms of cardiac contractile failure.
    Keywords:  Adeno-associated virus serotype 9 (AAV9); Gene therapy; RNAi; TRPM4; Transient receptor potential (TRP) channel
    DOI:  https://doi.org/10.1007/s00424-021-02521-6
  34. J Mol Cell Cardiol. 2021 Feb 04. pii: S0022-2828(21)00026-2. [Epub ahead of print]154 32-40
    Computational modeling approaches to cAMP/PKA signaling in cardiomyocytes.
    Kimberly J McCabe, Padmini Rangamani.
      The cAMP/PKA pathway is a fundamental regulator of excitation-contraction coupling in cardiomyocytes. Activation of cAMP has a variety of downstream effects on cardiac function including enhanced contraction, accelerated relaxation, adaptive stress response, mitochondrial regulation, and gene transcription. Experimental advances have shed light on the compartmentation of cAMP and PKA, which allow for control over the varied targets of these second messengers and is disrupted in heart failure conditions. Computational modeling is an important tool for understanding the spatial and temporal complexities of this system. In this review article, we outline the advances in computational modeling that have allowed for deeper understanding of cAMP/PKA dynamics in the cardiomyocyte in health and disease, and explore new modeling frameworks that may bring us closer to a more complete understanding of this system. We outline various compartmental and spatial signaling models that have been used to understand how β-adrenergic signaling pathways function in a variety of simulation conditions. We also discuss newer subcellular models of cardiovascular function that may be used as templates for the next phase of computational study of cAMP and PKA in the heart, and outline open challenges which are important to consider in future models.
    Keywords:  (Cyclic AMP); (Heart failure); (Multiscale modeling); (Systems biology); (β-adrenergic signaling)
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.01.008
  35. J Biol Regul Homeost Agents. 2021 Feb 08. 35(1):
    Protective effects of NLRP3 inhibitor MCC950 on sepsis-induced myocardial dysfunction.
    S Li, Z Guo, Z Y Zhang.
      Sepsis-induced myocardial dysfunction (SIMD) leads to poor prognosis or even death in severe sepsis cases, therefore, exploring its pathogenesis and new therapeutic targets has become the focus of current research. Specifically, an SIMD rat model was constructed by cecal ligation and puncture (CLP) method. At 24 h after intraperitoneal injection of the NLRP3 selective inhibitor MCC950, the levels of serum cardiac troponin I (cTnI) and Lactate dehydrogenase (LDH) in serum were detected, and the cardiac function of rats was examined via echocardiography. In addition, the pathological changes of myocardial tissues were observed by histological method, and the expression changes of inflammatory factors were detected in the tissue and serum. At the same time, H9C2 cells were treated with lipopolysaccharide (LPS) to simulate the in vitro model, and the expressions of inflammation and pyroptosis-related factors were detected. The results manifested that in the CLP group, the levels of serum cTnI and LDH were obviously increased, the myocardial tissue structure was disordered, the cell edema was severe, and the cardiac function was markedly reduced. Meanwhile, the expressions of inflammatory factors IL-6, IL-8 and TNF-α rose remarkably. On the contrary, MCC950 effectively reversed the above situation. Moreover, MCC950 inhibited LPS-induced inflammation and pyroptosis of H9C2 cells. In conclusion, the NLRP3 inhibitor MCC950 can reduce the release of LDH and other cellular inflammatory factors in the cytoplasm, thereby improving the cardiac function and slowing down the apoptosis of cardiomyocytes, which may be related to the inhibition of NLRP3/Caspase-1/IL-1β pathway.
    Keywords:  MCC950; NLRP3/Caspase-1/IL-1β pathway; inflammation; pyroptosis; sepsis-induced myocardial dysfunction
    DOI:  https://doi.org/10.23812/20-662-A
  36. Free Radic Res. 2021 Feb 09. 1-19
    Growth differentiation factor 11 mitigates cardiac radiotoxicity via activating AMPKα.
    Xia Li, Dong Ding, Wei Chen, Yu Liu, Haisong Pan, Jun Hu.
      Cardiac radiotoxicity largely impedes the therapeutic benefits of radiotherapy to malignancies. Growth differentiation factor 11 (GDF11) is implicated in the pathogenesis of cardiac diseases under different pathological conditions. The present study aims to investigate the role and underlying mechanisms of GDF11 on cardiac radiotoxicity. Mice were injected with cardiotropic adeno-associated virus 9 carrying the full-length mouse GDF11 gene or negative control under a cTnT promoter from the tail vein, and then received a single dose of 20 Gray whole-heart irradiation (WHI) for 16 weeks to imitate cardiac radiotoxicity. Compound C (CC, 20 mg/kg) was intraperitoneally injected every two days at 1 week before WHI stimulation to inhibit 5' AMP-activated protein kinase α (AMPKα). Cardiac GDF11 expression was significantly suppressed at both the protein and mRNA levels. GDF11 overexpression decreased oxidative stress, apoptosis and fibrosis in radiated hearts, thereby mitigating cardiac radiotoxicity and dysfunction. Further detection revealed that GDF11 activated AMPKα to reduce radiation-induced oxidative damage and that AMPKα inhibition by CC offset the cardioprotective effects by GDF11. GDF11 mitigates cardiac radiotoxicity via activating AMPKα and it is a promising candidate to treat cardiac radiotoxicity.
    Keywords:  AMPKα; Cardiac radiotoxicity; Fibrosis; GDF11; Oxidative damage
    DOI:  https://doi.org/10.1080/10715762.2021.1885653
  37. Ann Palliat Med. 2021 Feb 02. pii: apm-19-516. [Epub ahead of print]
    Scutellarin protects against diabetic cardiomyopathy via inhibiting oxidative stress and inflammatory response in mice.
    Lijiao Xu, Rongchang Chen, Xu Zhang, Yue Zhu, Xiaoyu Ma, Guibo Sun, Xiaobo Sun.
      BACKGROUND: Scutellarin (Scu) shows both anti-inflammatory and antioxidant activities. The study investigates cardioprotective effects of Scu in mice with type 1 diabetes and the underlying molecular mechanism.METHODS: Streptozotocin (STZ) was used to induce diabetic cardiomyopathy (DCM) in C57BL/6 mice by intraperitoneal injection (i.p.). Normal and diabetic mice were divided into 6 groups: control, diabetic model group (DM), DM + Scu (5 mg/kg), DM + Scu (10 mg/kg), DM + Scu (20 mg/kg), DM + pioglitazone (Pio) (10 mg/kg). Scu was administered to the mice intraperitoneally and Pio was administrated by oral. Mice in control and DM groups were simply treated normal saline. Four weeks later, myocardial function, myocardial fibrosis, the levels inflammatory factors and oxidative stress were detected.
    RESULTS: Scu improved cardiac function and reduced heart injury in diabetic mice, which was indicated by increasing Left ventricular (LV) end-diastolic volume (LVVd), fractional shortening (FS), and ejection fraction (EF) levels and decreased pathological changes of heart. Scu inhibited the level of myocardial fibrosis by reducing the release of inflammatory cytokines and increasing activities of antioxidant enzymes. Further study showed that Scu inhibited the activation of nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) and nuclear factor-kappa B (NF-κB) and activated phospho-protein kinase B (p-AKT), nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase (HO-1).
    CONCLUSIONS: Scu protects against DCM in STZ-induced diabetic mice by inhibiting oxidative stress and inflammatory responses and might be a potential therapeutic agent to treat DCM.
    Keywords:  Scutellarin (Scu); anti-inflammatory; anti-oxidative stress; diabetic cardiomyopathy (DCM)
    DOI:  https://doi.org/10.21037/apm-19-516
  38. Front Cell Dev Biol. 2020 ;8 609493
    Metformin Reverses the Enhanced Myocardial SR/ER-Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice.
    Claire Angebault, Mathieu Panel, Mathilde Lacôte, Jennifer Rieusset, Alain Lacampagne, Jérémy Fauconnier.
      Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca2+) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)-mitochondria interactions and mitochondrial function were impaired in dystrophic heart at the early stage of the pathology. For this purpose, ventricular cardiomyocytes and mitochondria were isolated from 3-month-old dystrophin-deficient mice (mdx mice). The number of contacts points between the SR/ER Ca2+ release channels (IP3R1) and the porine of the outer membrane of the mitochondria, VDAC1, measured using in situ proximity ligation assay, was greater in mdx cardiomyocytes. Expression levels of IP3R1 as well as the mitochondrial Ca2+ uniporter (MCU) and its regulated subunit, MICU1, were also increased in mdx heart. MICU2 expression was however unchanged. Furthermore, the mitochondrial Ca2+ uptake kinetics and the mitochondrial Ca2+ content were significantly increased. Meanwhile, the Ca2+-dependent pyruvate dehydrogenase phosphorylation was reduced, and its activity significantly increased. In Ca2+-free conditions, pyruvate-driven complex I respiration was decreased whereas in the presence of Ca2+, complex I-mediated respiration was boosted. Further, impaired complex I-mediated respiration was independent of its intrinsic activity or expression, which remains unchanged but is accompanied by an increase in mitochondrial reactive oxygen species production. Finally, mdx mice were treated with the complex I modulator metformin for 1 month. Metformin normalized the SR/ER-mitochondria interaction, decreased MICU1 expression and mitochondrial Ca2+ content, and enhanced complex I-driven respiration. In summary, before any sign of dilated cardiomyopathy, the DMD heart displays an aberrant SR/ER-mitochondria coupling with an increase mitochondrial Ca2+ homeostasis and a complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.
    Keywords:  Duchenne muscular dystrophy cardiomyopathy; MICU1; calcium; mitochondria-associated ER membrane; mitochondrial calcium uniporter
    DOI:  https://doi.org/10.3389/fcell.2020.609493
  39. Eur Rev Med Pharmacol Sci. 2021 Jan;pii: 24647. [Epub ahead of print]25(2): 820-836
    Protective effect of MAPK signaling pathway mediated by ITGB3 gene silencing on myocardial ischemia-reperfusion injury in mice and its mechanism.
    M-C Wang, D Wang, Y-H Lu, Z-H Li, H-Y Jing.
      OBJECTIVE: To explore the effect of integrin β3 (ITGB3) gene silencing mediated mitogen-activated protein kinase (MAPK) signaling pathway on myocardial ischemia-reperfusion injury (MIRI) in mice.MATERIALS AND METHODS: MIRI mice model was established, and myocardial tissues of MIRI mice and sham operation group mice were extracted. Hematoxylin-Eosin (HE) staining was used to observe the pathological changes of myocardial tissue; terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was used to detect the apoptosis of myocardial cells; ELISA method was used to detect the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α in the two groups. The infarct size was measured by TTC staining. Myocardial cells of MIRI model mice were isolated and cultured, and then grouped and transfected. The cells were transfected with the grouping of MIRI group, negative control (NC) group, MAPK signal pathway agonist Anisomycin group, MAPK signal pathway inhibitor SB203580 group, ITGB3-siRNA group, SB203580 + ITGB3-siRNA group. Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot were used to detect the mRNA and protein expressions of ITGB3, p38MAPK/p-p38MAPK, GSK-3β/p-GSK-3β, Cx43/p-Cx43, pro-apoptotic factor Bax and anti-apoptotic factor Bcl-2. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay was used to detect cell proliferation and flow cytometry to detect cell apoptosis.
    RESULTS: The expression of ITGB3 in myocardial tissue of MIRI mice was significantly higher than that of sham operated mice (p<0.05). Compared with the sham operation group, the apoptosis rate of myocardial cells in MIRI group was significantly increased, the expression levels of IL-1, IL-6 and TNF-α were significantly increased, and the myocardial infarction area was significantly increased (all p<0.05). Compared with MIRI and NC groups, ITGB3 mRNA and protein expression levels in ITGB3-siRNA group and SB203580 + ITGB3-siRNA group were significantly decreased (all p<0.05), but no significant change was found in Anisomycin group and SB203580 group (p>0.05). Furthermore, ITGB3-siRNA group and Anisomycin group had markedly decreased mRNA and protein expressions of ITGB3 and Bax, increased mRNA and protein expressions of p38MAPK/p-p38MAPK, GSK-3β/p-GSK-3β, Cx43/p-Cx43 and Bcl-2, as well as increased cell proliferation and decreased cell apoptosis (all p<0.05); SB203580 group indicated an opposite result with Anisomycin group; while SB203580 + ITGB3-siRNA revealed none significant statistical difference. In addition, compared with ITGB3-siRNA group, SB203580 + ITGB3-siRNA group showed significantly upregulated mRNA and protein expressions of Bax, downregulated mRNA and protein expressions of p38MAPK/p-p38MAPK, GSK-3β/p-GSK-3β, Cx43/p-Cx43 and Bcl-2, as well as decreased cell proliferation and increased cell apoptosis (all p<0.05).
    CONCLUSIONS: Silencing ITGB3 gene expression can promote the activation of MAPK signaling pathway, elevate the phosphorylation of GSK-3β and Cx43 in the downstream, promote the proliferation of mouse myocardial cells, inhibit myocardial cell apoptosis and inflammatory reaction, and thus have protective effect on MIRI in mice.
    DOI:  https://doi.org/10.26355/eurrev_202101_24647
  40. Mol Med. 2021 Feb 10. 27(1): 13
    Elevated MST1 leads to apoptosis via depletion of YAP1 in cardiomyocytes exposed to high glucose.
    Dongmei Su, Yanhua Li, Lina Guan, Qian Li, Cuige Shi, Xu Ma, Yonghui Song.
      BACKGROUND: Gestational diabetes mellitus is a risk factor for congenital heart defects. The article aimed to investigate the expression and roles of MST1, YAP1, Last1/2 and Survivin in modulating HG-induced cardiomyocyte apoptosis and maternal diabetes-induced heart abnormality.METHODS: Diabetes mellitus was induced in rats using streptozotocin. The protein expression and phosphorylation analysis in fetal heart tissue was assessed by western blot and immunohistochemical staining. Hoechst 33342 staining assay was performed to explore H9C2 apoptosis. The gene and protein expression in H9C2 cells was assessed by quantitative PCR and western blot. Knockdown of gene expression was assessed by RNA interference.
    RESULTS: Our results revealed that increased MST1 protein levels in the heart tissues of the offspring of diabetic rats in vivo and in H9C2 cardiomyocytes under HG treatment in vitro, respectively. Knockdown and overexpression experiments showed that MST1 played a key role in mediating HG-induced apoptosis in cardiomyocytes. Downregulation of YAP1 was associated with HG-induced, MST1-mediated cardiomyocyte apoptosis. Further study showed that MST1 downregulated the protein level of YAP1 through mediation of YAP1 phosphorylation on Ser127 and Ser397; this process also required LATS1/2 participation. MST1 overexpression increased the phosphorylation levels of LATS1/2, which were also shown to be increased in the heart tissues of diabetic offspring. We also found that YAP1 mediated the expression of Survivin during HG-induced apoptosis, and the Survivin-inhibitor YM155 partially inhibited the role of YAP1 in suppressing apoptosis induced by HG in cardiomyocytes.
    CONCLUSION: These findings reveal a regulatory mechanism of MST1/YAP1/Survivin signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.
    Keywords:  Cardiomyocyte apoptosis; High glucose; MST1; Survivin; YAP1
    DOI:  https://doi.org/10.1186/s10020-021-00267-6
  41. Front Cardiovasc Med. 2020 ;7 588347
    Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players.
    Somayeh Saadat, Mahdi Noureddini, Maryam Mahjoubin-Tehran, Sina Nazemi, Layla Shojaie, Michael Aschner, Behnaz Maleki, Mohammad Abbasi-Kolli, Hasan Rajabi Moghadam, Behrang Alani, Hamed Mirzaei.
      Unintended cardiac fibroblast proliferation in many pathophysiological heart conditions, known as cardiac fibrosis, results in pooling of extracellular matrix (ECM) proteins in the heart muscle. Transforming growth factor β (TGF-β) as a pivotal cytokine/growth factor stimulates fibroblasts and hastens ECM production in injured tissues. The TGF-β receptor is a heterodimeric receptor complex on the plasma membrane, made up from TGF-β type I, as well as type II receptors, giving rise to Smad2 and Smad3 transcription factors phosphorylation upon canonical signaling. Phosphorylated Smad2, Smad3, and cytoplasmic Smad4 intercommunicate to transfer the signal to the nucleus, culminating in provoked gene transcription. Additionally, TGF-β receptor complex activation starts up non-canonical signaling that lead to the mitogen-stimulated protein kinase cascade activation, inducing p38, JNK1/2 (c-Jun NH2-terminal kinase 1/2), and ERK1/2 (extracellular signal-regulated kinase 1/2) signaling. TGF-β not only activates fibroblasts and stimulates them to differentiate into myofibroblasts, which produce ECM proteins, but also promotes fibroblast proliferation. Non-coding RNAs (ncRNAs) are important regulators of numerous pathways along with cellular procedures. MicroRNAs and circular long ncRNAs, combined with long ncRNAs, are capable of affecting TGF-β/Smad signaling, leading to cardiac fibrosis. More comprehensive knowledge based on these processes may bring about new diagnostic and therapeutic approaches for different cardiac disorders.
    Keywords:  Smad; TGF—transforming growth factor; cardiac fibrosis; microRNA; non-coding RNAs
    DOI:  https://doi.org/10.3389/fcvm.2020.588347
  42. Cell Biosci. 2021 Feb 06. 11(1): 31
    The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure.
    Jingtao Na, Haifeng Jin, Xin Wang, Kan Huang, Shuang Sun, Qiang Li, Wenting Zhang.
      BACKGROUND: Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating  targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3.METHODS: Firstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-β1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry.
    RESULTS: HDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and -dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined.
    CONCLUSION: Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.
    Keywords:  ADRB3; Fibrosis; HDAC3; Heart failure; Hypertrophy; microRNA-18a
    DOI:  https://doi.org/10.1186/s13578-020-00523-y
  43. J Mol Cell Cardiol. 2021 Feb 05. pii: S0022-2828(21)00025-0. [Epub ahead of print]154 41-59
    Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein.
    Sriram Aravamudhan, Clara Türk, Theresa Bock, Lena Keufgens, Hendrik Nolte, Franziska Lang, Ramesh Kumar Krishnan, Tim König, Philipp Hammerschmidt, Natalie Schindler, Susanne Brodesser, Dieu Hien Rozsivalova, Elena Rugarli, Aleksandra Trifunovic, Jens Brüning, Thomas Langer, Thomas Braun, Marcus Krüger.
      Heart development relies on PTMs that control cardiomyocyte proliferation, differentiation and cardiac morphogenesis. We generated a map of phosphorylation sites during the early stages of cardiac postnatal development in mice; we quantified over 10,000 phosphorylation sites and 5000 proteins that were assigned to different pathways. Analysis of mitochondrial proteins led to the identification of PGC-1- and ERR-induced regulator in muscle 1 (PERM1), which is specifically expressed in skeletal muscle and heart tissue and associates with the outer mitochondrial membrane. We demonstrate PERM1 is subject to rapid changes mediated by the UPS through phosphorylation of its PEST motif by casein kinase 2. Ablation of Perm1 in mice results in reduced protein expression of lipin-1 accompanied by accumulation of specific phospholipid species. Isolation of Perm1-deficient mitochondria revealed significant downregulation of mitochondrial transport proteins for amino acids and carnitines, including SLC25A12/13/29/34 and CPT2. Consistently, we observed altered levels of various lipid species, amino acids, and acylcarnitines in Perm1-/- mitochondria. We conclude that the outer mitochondrial membrane protein PERM1 regulates homeostasis of lipid and amino acid metabolites in mitochondria.
    Keywords:  Heart development; Lipid metabolism; Mitochondria; PERM1; Phosphoproteomics; SILAC
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.01.010
  44. Sci Rep. 2021 Feb 11. 11(1): 3588
    Smad4 regulates the nuclear translocation of Nkx2-5 in cardiac differentiation.
    Wenyu Hu, Anqi Dong, Kohei Karasaki, Shota Sogabe, Daiki Okamoto, Masato Saigo, Mari Ishida, Masao Yoshizumi, Hiroki Kokubo.
      Bmp plays an important role in cardiomyocyte differentiation, but the function of Smad4 in Bmp signaling remains elusive. Here, we show that disruption of the Smad4 gene in cardiac progenitors expressing Sfrp5 led to embryonic lethality with hypoplastic heart formation. Although the expression of Nkx2-5 is regulated by Bmp signaling, expression of Nkx2-5 was weakly detected in the mutant heart. However, the nuclear translocation of Nkx2-5 was impaired. Expression of CK2 or PP1, which could alter the phosphorylation status of the NLS of Nkx2-5, was not affected, but Nkx2-5 was found to bind to Smad4 by co-immunoprecipitation experiments. Introduction of Smad4 into cells derived from Smad4 conditional knockout embryonic hearts restored the nuclear localization of Nkx2-5, and exogenous Nkx2-5 failed to translocate into the nucleus of Smad4-depleted fibroblasts. These results suggest that Smad4 plays an essential role in cardiomyocyte differentiation by controlling not only transcription but also the nuclear localization of Nkx2-5.
    DOI:  https://doi.org/10.1038/s41598-021-82954-2
  45. J Mol Cell Cardiol. 2021 Feb 05. pii: S0022-2828(21)00023-7. [Epub ahead of print]
    Rad-GTPase contributes to heart rate via L-type calcium channel regulation.
    Bryana M Levitan, Brooke M Ahern, Ajoy Aloysius, Laura Brown, Yuan Wen, Douglas A Andres, Jonathan Satin.
      Sinoatrial node cardiomyocytes (SANcm) possess automatic, rhythmic electrical activity. SAN rate is influenced by autonomic nervous system input, including sympathetic nerve increases of heart rate (HR) via activation of β-adrenergic receptor signaling cascade (β-AR). L-type calcium channel (LTCC) activity contributes to membrane depolarization and is a central target of β-AR signaling. Recent studies revealed that the small G-protein Rad plays a central role in β-adrenergic receptor directed modulation of LTCC. These studies have identified a conserved mechanism in which β-AR stimulation results in PKA-dependent Rad phosphorylation: depletion of Rad from the LTCC complex, which is proposed to relieve the constitutive inhibition of CaV1.2 imposed by Rad association. Here, using a transgenic mouse model permitting conditional cardiomyocyte selective Rad ablation, we examine the contribution of Rad to the control of SANcm LTCC current (ICa,L) and sinus rhythm. Single cell analysis from a recent published database indicates that Rad is expressed in SANcm, and we show that SANcm ICa,L was significantly increased in dispersed SANcm following Rad silencing compared to those from CTRL hearts. Moreover, cRadKO SANcm ICa,L was not further increased with β-AR agonists. We also evaluated heart rhythm in vivo using radiotelemetered ECG recordings in ambulating mice. In vivo, intrinsic HR is significantly elevated in cRadKO. During the sleep phase cRadKO also show elevated HR, and during the active phase there is no significant difference. Rad-deletion had no significant effect on heart rate variability. These results are consistent with Rad governing LTCC function under relatively low sympathetic drive conditions to contribute to slower HR during the diurnal sleep phase HR. In the absence of Rad, the tonic modulated SANcm ICa,L promotes elevated sinus HR. Future novel therapeutics for bradycardia targeting Rad - LTCC can thus elevate HR while retaining βAR responsiveness.
    Keywords:  Cardiomyocyte; Heart rate regulation; Heart rhythm; L-type calcium channel
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.01.005
  46. Commun Biol. 2021 Feb 12. 4(1): 188
    Amylin deposition activates HIF1α and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates.
    Miao Liu, Nan Li, Chun Qu, Yilin Gao, Lijie Wu, Liangbiao George Hu.
      Hyperamylinemia induces amylin aggregation and toxicity in the pancreas and contributes to the development of type-2 diabetes (T2D). Cardiac amylin deposition in patients with obesity and T2D was found to accelerate heart dysfunction. Non-human primates (NHPs) have similar genetic, metabolic, and cardiovascular processes as humans. However, the underlying mechanisms of cardiac amylin in NHPs, particularly related to the hypoxia inducible factor (HIF)1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathways, are unknown. Here, we demonstrate that in NHPs, amylin deposition in heart failure (HF) contributes to cardiac dysfunction via activation of HIF1α and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca2+, reactive oxygen species, mitochondrial function, and lactate levels were observed in amylin-treated cells. Our study demonstrates a pathological role for amylin in the activation of HIF1α and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.
    DOI:  https://doi.org/10.1038/s42003-021-01676-3
  47. Can J Physiol Pharmacol. 2021 Feb 09. 1-11
    Role of prostaglandin E2 in allogeneic mesenchymal stem cell therapy for cardiac repair.
    Niketa Sareen, Abhay Srivastava, Sanjiv Dhingra.
      Ischemic heart disease is among the primary causes of cardiovascular-related deaths worldwide. Conventional treatments including surgical interventions and medical therapies aid in preventing further damage to heart muscle but are unable to provide a permanent solution. In recent years, stem cell therapy has emerged as an attractive alternative to restore damaged myocardium after myocardial injury. Allogeneic (donor-derived) mesenchymal stem cells (MSCs) have shown great promise in preclinical and clinical studies, making them the most widely accepted candidates for cardiac cell therapy. MSCs promote cardiac repair by modulating host immune system and secreting various soluble factors, of which prostaglandin E2 (PGE2) is an important one. PGE2 plays a significant role in regulating cardiac remodeling following myocardial injury. In this review, we provide an overview of allogeneic MSCs as candidates for myocardial regeneration with a focus on the role of the PGE2/cyclooxygenase-2 (COX2) pathway in mediating these effects.
    Keywords:  COX2; PGE2; cardiac ischemia; cell therapy; cellules souches mésenchymateuses; immunoprivilege; immunoprivilège; ischémie cardiaque; mesenchymal stem cells; thérapie cellulaire
    DOI:  https://doi.org/10.1139/cjpp-2020-0413
  48. J Mol Cell Cardiol. 2021 Feb 05. pii: S0022-2828(21)00029-8. [Epub ahead of print]
    β1-adrenergic receptor N-terminal cleavage by ADAM17; the mechanism for redox-dependent downregulation of cardiomyocyte β1-adrenergic receptors.
    Jing Zhu, Susan F Steinberg.
      β1-adrenergic receptors (β1ARs) are the principle mediators of catecholamine action in cardiomyocytes. We previously showed that the β1AR extracellular N-terminus is a target for post-translational modifications that impact on signaling responses. Specifically, we showed that the β1AR N-terminus carries O-glycan modifications at Ser37/Ser41, that O-glycosylation prevents β1AR N-terminal cleavage, and that N-terminal truncation influences β1AR signaling to downstream effectors. However, the site(s) and mechanism for β1AR N-terminal cleavage in cells was not identified. This study shows that β1ARs are expressed in cardiomyocytes and other cells types as both full-length and N-terminally truncated species and that the truncated β1AR species is formed as a result of an O-glycan regulated N-terminal cleavage by ADAM17 at R31↓L32. We identify Ser41 as the major O-glycosylation site on the β1AR N-terminus and show that an O-glycan modification at Ser41 prevents ADAM17-dependent cleavage of the β1-AR N-terminus at S41↓L42, a second N-terminal cleavage site adjacent to this O-glycan modification (and it attenuates β1-AR N-terminal cleavage at R31↓L32). We previously reported that oxidative stress leads to a decrease in β1AR expression and catecholamine responsiveness in cardiomyocytes. This study shows that redox-inactivation of cardiomyocyte β1ARs is via a mechanism involving N-terminal truncation at R31↓L32 by ADAM17. In keeping with the previous observation that N-terminally truncated β1ARs constitutively activate an AKT pathway that affords protection against doxorubicin-dependent apoptosis, overexpression of a cleavage resistant β1AR mutant exacerbates doxorubicin-dependent apoptosis. These studies identify the β1AR N-terminus as a structural determinant of β1AR responses that can be targeted for therapeutic advantage.
    Keywords:  ADAM17; Cardiomyocytes; Glycosylation; Oxidant stress; β-Adrenergic receptor
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.01.012
  49. Cardiovasc Res. 2021 Feb 08. pii: cvab045. [Epub ahead of print]
    Tbx5 variants disrupt Nav1.5 function differently in patients diagnosed with Brugada or Long QT Syndrome.
    Paloma Nieto-Marín, David Tinaquero, Raquel G Utrilla, Jorge Cebrián, Andrés González-Guerra, Teresa Crespo-García, Anabel Cámara-Checa, Marcos Rubio-Alarcón, María Dago, Silvia Alfayate, David Filgueiras, Rafael Peinado, José Luis López-Sendón, José Jalife, Juan Tamargo, Juan Antonio Bernal, Ricardo Caballero, Eva Delpón, .
      AIMS: The transcription factor Tbx5 controls cardiogenesis and drives Scn5a expression in mice. We have identified two variants in TBX5 encoding p.D111Y and p.F206L Tbx5, respectively, in two unrelated patients with structurally normal hearts diagnosed with Long QT (LQTS) and Brugada (BrS) Syndrome. Here we characterized the consequences of each variant to unravel the underlying disease mechanisms.METHODS AND RESULTS: We combined clinical analysis with in vivo and in vitro electrophysiological and molecular techniques in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), HL-1 cells, and cardiomyocytes from mice trans-expressing human wildtype (WT) or mutant proteins. Tbx5 increased transcription of SCN5A encoding cardiac Nav1.5 channels, while repressing CAMK2D and SPTBN4 genes encoding Ca-calmodulin kinase IIδ (CaMKIIδ) and βIV-spectrin, respectively. These effects significantly increased Na current (INa) in hiPSC-CMs and in cardiomyocytes from mice trans-expressing Tbx5. Consequently, action potential (AP) amplitudes increased and QRS interval narrowed in the mouse electrocardiogram. p.F206L Tbx5 bound to the SCN5A promoter failed to transactivate it, thus precluding the pro-transcriptional effect of WT Tbx5. Therefore, p.F206L markedly decreased INa in hiPSC-CM, HL-1 cells, and mouse cardiomyocytes. The INa decrease in p.F206L trans-expressing mice translated into QRS widening and increased flecainide sensitivity. p.D111Y Tbx5 increased SCN5A expression but failed to repress CAMK2D and SPTBN4. The increased CaMKIIδ and βIV-spectrin significantly augmented the late component of INa (INaL) which, in turn, significantly prolonged AP duration in both hiPSC-CMs and mouse cardiomyocytes. Ranolazine, a selective INaL inhibitor, eliminated the QT and QTc intervals prolongation seen in p.D111Y trans-expressing mice.
    CONCLUSIONS: In addition to peak INa, Tbx5 critically regulates INaL and the duration of repolarization in human cardiomyocytes. Our original results suggest that TBX5 variants associate with and modulate the intensity of the electrical phenotype in LQTS and BrS patients.
    Keywords:  Ca Calmodulin kinase II; Inherited arrhythmogenic Syndromes; Nav1.5; Tbx5; βIV-Spectrin
    DOI:  https://doi.org/10.1093/cvr/cvab045
  50. ACS Infect Dis. 2021 Feb 11.
    Wnt Signaling Plays a Key Role in the Regulation of the Immune Response and Cardiac Damage during Trypanosoma cruzi Infection.
    Ximena Volpini, Laura Fernanda Ambrosio, María Agustina Brajín, María Belen Brugo, María Pilar Aoki, Hector Walter Rivarola, Fernando Alfonso, Laura Fozzatti, Laura Cervi, Claudia Cristina Motran.
      Chagas cardiomyopathy is the consequence of a compromised electrical and mechanical cardiac function, with parasite persistence, unbalanced inflammation, and pathological tissue remodelling, being intricately related to myocardial aggression and impaired function. Recent studies have shown that Wnt signaling pathways play a critical role in the pathogenesis of cardiac and vascular diseases. In addition, we have reported that Trypanosoma cruzi infection activates Wnt signaling to promote intracellular replication of the parasites in macrophages, with the treatment of mice with IWP-L6 (an inhibitor of the O-acyl-transferase, PORCN, responsible for the post-translational modifications necessary for Wnt protein secretion) being able to diminish parasitemia and tissue parasitism. Here, we show that inhibition of Wnt signaling during the acute phase of T. cruzi infection controls the parasite replication, inhibits the development of parasite-prone and fibrosis-prone Th2-type immune response, and prevents the development of cardiac abnormalities characteristics of chronic Chagas disease. Our results suggest that the Wnt signaling pathway might be a potential target to prevent the development of T. cruzi-induced cardiomyopathy.
    Keywords:  Chagas disease; Th1/Th2 balance; antibody; cardiomyopathy; regulatory T cells
    DOI:  https://doi.org/10.1021/acsinfecdis.0c00590
  51. Signal Transduct Target Ther. 2021 Feb 09. 6(1): 54
    Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis.
    Sha Xu, Hui Tao, Wei Cao, Li Cao, Yan Lin, Shi-Min Zhao, Wei Xu, Jing Cao, Jian-Yuan Zhao.
      In addition to their use in relieving the symptoms of various diseases, ketogenic diets (KDs) have also been adopted by healthy individuals to prevent being overweight. Herein, we reported that prolonged KD exposure induced cardiac fibrosis. In rats, KD or frequent deep fasting decreased mitochondrial biogenesis, reduced cell respiration, and increased cardiomyocyte apoptosis and cardiac fibrosis. Mechanistically, increased levels of the ketone body β-hydroxybutyrate (β-OHB), an HDAC2 inhibitor, promoted histone acetylation of the Sirt7 promoter and activated Sirt7 transcription. This in turn inhibited the transcription of mitochondrial ribosome-encoding genes and mitochondrial biogenesis, leading to cardiomyocyte apoptosis and cardiac fibrosis. Exogenous β-OHB administration mimicked the effects of a KD in rats. Notably, increased β-OHB levels and SIRT7 expression, decreased mitochondrial biogenesis, and increased cardiac fibrosis were detected in human atrial fibrillation heart tissues. Our results highlighted the unknown detrimental effects of KDs and provided insights into strategies for preventing cardiac fibrosis in patients for whom KDs are medically necessary.
    DOI:  https://doi.org/10.1038/s41392-020-00411-4
  52. Nat Commun. 2021 02 08. 12(1): 873
    Individualized interactomes for network-based precision medicine in hypertrophic cardiomyopathy with implications for other clinical pathophenotypes.
    Bradley A Maron, Rui-Sheng Wang, Sergei Shevtsov, Stavros G Drakos, Elena Arons, Omar Wever-Pinzon, Gordon S Huggins, Andriy O Samokhin, William M Oldham, Yasmine Aguib, Magdi H Yacoub, Ethan J Rowin, Barry J Maron, Martin S Maron, Joseph Loscalzo.
      Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine.
    DOI:  https://doi.org/10.1038/s41467-021-21146-y
  53. Dev Biol. 2021 Feb 09. pii: S0012-1606(21)00034-8. [Epub ahead of print]
    The role of glucose in physiological and pathological heart formation.
    Haruko Nakano, Viviana M Fajardo, Atsushi Nakano.
      Cells display distinct metabolic characteristics depending on its differentiation stage. The fuel type of the cells serves not only as a source of energy but also as a driver of differentiation. Glucose, the primary nutrient to the cells, is a critical regulator of rapidly growing embryos. This metabolic change is a consequence as well as a cause of changes in genetic program. Disturbance of fetal glucose metabolism such as diabetic pregnancy is associated with congenital heart disease. In utero hyperglycemia impacts the left-right axis establishment, migration of cardiac neural crest cells, conotruncal formation and mesenchymal formation of the cardiac cushion during early embryogenesis and causes cardiac hypertrophy in late fetal stages. In this review, we focus on the role of glucose in cardiogenesis and the molecular mechanisms underlying heart diseases associated with hyperglycemia.
    DOI:  https://doi.org/10.1016/j.ydbio.2021.01.020
  54. Oxid Med Cell Longev. 2021 ;2021 8863789
    Role of Oxidative Stress in the Mechanisms of Anthracycline-Induced Cardiotoxicity: Effects of Preventive Strategies.
    Rodrigo Carrasco, Rodrigo L Castillo, Juan G Gormaz, Montserrat Carrillo, Paaladinesh Thavendiranathan.
      Anthracycline-induced cardiotoxicity (AIC) persists as a significant cause of morbidity and mortality in cancer survivors. Although many protective strategies have been evaluated, cardiotoxicity remains an ongoing threat. The mechanisms of AIC remain unclear; however, several pathways have been proposed, suggesting a multifactorial origin. When the central role of topoisomerase 2β in the pathophysiology of AIC was described some years ago, the classical reactive oxygen species (ROS) hypothesis shifted to a secondary position. However, new insights have reemphasized the importance of the role of oxidative stress-mediated signaling as a common pathway and a critical modulator of the different mechanisms involved in AIC. A better understanding of the mechanisms of cardiotoxicity is crucial for the development of treatment strategies. It has been suggested that the available therapeutic interventions for AIC could act on the modulation of oxidative balance, leading to a reduction in oxidative stress injury. These indirect antioxidant effects make them an option for the primary prevention of AIC. In this review, our objective is to provide an update of the accumulated knowledge on the role of oxidative stress in AIC and the modulation of the redox balance by potential preventive strategies.
    DOI:  https://doi.org/10.1155/2021/8863789
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:18:58.