bims-cesiha 2021-03-07 papers

bims-cesiha

Biomed News

on Cell signalling in the heart

Issue of 2021‒03‒07
thirty-five papers selected by
Danae Angelidaki
Max Planck Institute for Biology of Ageing

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.
Limb-bud and Heart (LBH) mediates proliferation, fibroblast-to-myofibroblast transition and EMT-like processes in cardiac fibroblasts.
Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration.
Txnip C247S mutation protects the heart against acute myocardial infarction.
SAIL: a new conserved anti-fibrotic lncRNA in the heart.
Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p.
The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1 axis-mediated mitochondrial dynamics.
Impact of PCSK9 on CTRP9-Induced Metabolic Effects in Adult Rat Cardiomyocytes.
Activation of amino acid metabolic program in cardiac HIF1-alpha-deficient mice.
Effects of Hsp90 inhibitor on the RIP1-RIP3-MLKL pathway during the development of heart failure in mice.
Toll-like receptor 2 signaling deficiency in cardiac cells ameliorates Ang II-induced cardiac inflammation and remodeling.
Sirt1 and Sirt3 Activation Improved Cardiac Function of Diabetic Rats via Modulation of Mitochondrial Function.
Selective Cardiomyocyte Oxidative Stress Leads to Bystander Senescence of Cardiac Stromal Cells.
Pharmacological Pre- and Postconditioning With Levosimendan Protect H9c2 Cardiomyoblasts From Anoxia/Reoxygenation-induced Cell Death via PI3K/Akt Signaling.
Rosuvastatin corrects oxidative stress and inflammation induced by LPS to attenuate cardiac injury by inhibiting the NLRP3/TLR4 pathway.
Qiliqiangxin alleviates Ang II-induced CMECs apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis.
The peroxisomal enzyme, FAR1, is induced during ER stress in an ATF6-dependent manner in cardiac myocytes.
Vitamin D3 Supplementation Alleviates Left Ventricular Dysfunction in a Mouse Model of Diet-Induced Type 2 Diabetes: Potential Involvement of Cardiac Lipotoxicity Modulation.
LncRNA HOTAIR Promotes LPS-Induced Inflammation and Apoptosis of Cardiomyocytes via Lin28-Mediated PDCD4 Stability.
A Roadmap to Heart Regeneration Through Conserved Mechanisms in Zebrafish and Mammals.
Suppression of Myocardial HIF-1α Compromises Metabolic Adaptation and Impairs Cardiac Function in Patients with Cyanotic Congenital Heart Disease During Puberty.
The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis.
Hyperoside protects cardiomyocytes against hypoxia‑induced injury via upregulation of microRNA‑138.
STAT3 Suppresses Cardiomyocytes Apoptosis in CVB3-Induced Myocarditis Via Survivin.
Cardiac MyBP-C phosphorylation regulates the Frank-Starling relationship in murine hearts.
Role of Adenosine and Purinergic Receptors in Myocardial Infarction: Focus on Different Signal Transduction Pathways.
Myocardial Hypertrophy and Compensatory Increase in Systolic Function in a Mouse Model of Oxidative Stress.
PTEN mediates serum deprivation-induced cytotoxicity in H9c2 cells via the PI3K/AKT signaling pathway.
Role of AMPK in the protective effects exerted by triiodothyronine in ischemic-reperfused myocardium.
Computational model of cardiomyocyte apoptosis identifies mechanisms of tyrosine kinase inhibitor-induced cardiotoxicity.
YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases.
Preconditioning with Short-term Dietary Restriction Attenuates Cardiac Oxidative Stress and Hypertrophy Induced by Chronic Pressure Overload.
Cardiac myosin binding protein-C phosphorylation accelerates β-cardiac myosin detachment rate in mouse myocardium.
Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling.
Effects of Apocynin on Heart Muscle Oxidative Stress of Rats with Experimental Diabetes: Implications for Mitochondria.

Circulation. 2021 Mar 05.

LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.

Huijing Yu, Fang Zhang, Pengyi Yan, Shasha Zhang, Yingmei Lou, Zilong Geng, Zixuan Li, Yan Zhang, Yuejuan Xu, Yanan Lu, Chen Chen, Daowen Wang, Wei Zhu, Xinyang Hu, Jian'an Wang, Tao Zhuang, Yuzhen Zhang, Gengze Wu, Junling Liu, Chunyu Zeng, William T Pu, Kun Sun, Bing Zhang.

  Background: Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. La ribonucleoprotein domain family member 7 (LARP7) is a master regulator that governs the DNA damage response and RNAPII pausing pathway, but the role of it in heart failure pathogenesis is incompletely understood. Methods: We assessed LARP7 expression in human HF, and in non-human primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 (AAV9) and ataxia telangiectasia mutated protein (ATM) inhibitor. The therapeutic potential of LARP7-regulated pathways in heart failure was tested in a mouse myocardial infarction model. Results: LARP7 was profoundly downregulated in failing human hearts and in non-human primate and murine hearts after myocardial infarction (MI). Low LARP7 levels in failing hearts was linked to elevated reactive oxygen species (ROS), which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 stability and deacetylase activity which impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after MI by either AAV-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart. Conclusions: LARP7 is essential for mitochondrial biogenesis, energy production and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts due to activation of the ATM pathway contributes to heart failure pathogenesis, and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in heart failure.

Keywords:  LARP7; Mitochondrial biogenesis

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.120.050812
Mol Cell Biochem. 2021 Mar 05.

Limb-bud and Heart (LBH) mediates proliferation, fibroblast-to-myofibroblast transition and EMT-like processes in cardiac fibroblasts.

Anbiao Wu, Lihong Zhang, Jingyang Chen, Hekai Li, Pingzhen Yang, Minsheng Chen, Qicai Liu.

  Cardiac fibrosis is an important pathological change after myocardial infarction (MI). Its progression is essential for post-MI infarct healing, during which transforming growth factor beta1 (TGF-β1) plays a critical role. Limb-bud and Heart (LBH), a newly discovered target gene of TGF-β1, was shown to promote normal cardiogenesis. αB-crystallin (CRYAB), an LBH-interacting protein, was demonstrated to be involved in TGF-β1-induced fibrosis. The roles and molecular mechanisms of LBH and CRYAB during cardiac fibrosis remain largely unexplored. In this study, we investigated the alterations of LBH and CRYAB expression in mouse cardiac tissue after MI. LBH and CRYAB were upregulated in activated cardiac fibroblasts (CFs), while in vitro TGF-β1 stimulation induced the upregulation of LBH, CRYAB, and fibrogenic genes in primary CFs of neonatal rats. The results of the ectopic expression of LBH proved that LBH accelerated CF proliferation under hypoxia, mediated the expression of CRYAB and fibrogenic genes, and promoted epithelial-mesenchymal transition (EMT)-like processes in rat CFs, while subsequent CRYAB silencing reversed the effects induced by elevated LBH expression. We also verified the protein-protein interaction (PPI) between LBH and CRYAB in fibroblasts. In summary, our work demonstrated that LBH promotes the proliferation of CFs, mediates TGF-β1-induced fibroblast-to-myofibroblast transition and EMT-like processes through CRYAB upregulation, jointly functioning in post-MI infarct healing. These findings suggest that LBH could be a promising potential target for the study of cardiac repair and cardiac fibrosis.

Keywords:  CRYAB; Cardiac fibroblasts; Fibroblast-to-myofibroblast transition; LBH; TGF-β1

DOI:  https://doi.org/10.1007/s11010-021-04111-7
Circulation. 2021 Mar 05.

Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration.

Jiyoung Bae, Rebecca J Salamon, Emma B Brandt, Wyatt G Paltzer, Ziheng Zhang, Emily C Britt, Timothy A Hacker, Jing Fan, Ahmed I Mahmoud.

  Background: Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species (ROS) production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in ROS production have been relatively unexplored. Current evidence suggests that elevated ROS production in ischemic tissues occurs due to accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Interestingly, mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear. Methods: Here, we investigated the role of succinate and succinate dehydrogenase (SDH) inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration. Results: Our results demonstrate that injection of succinate in neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart following myocardial infarction injury results in a robust regenerative response within 4 weeks following injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis following SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism. Conclusions: Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.

Keywords:  heart regeneration; succinate dehydrogenase

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.120.049952
J Mol Cell Cardiol. 2021 Feb 27. pii: S0022-2828(21)00048-1. [Epub ahead of print]

Txnip C247S mutation protects the heart against acute myocardial infarction.

Yoshinobu Nakayama, Nobuhiro Mukai, Bing F Wang, Kristen Yang, Parth Patwari, Richard N Kitsis, Jun Yoshioka.

  RATIONALE: Thioredoxin-interacting protein (Txnip) is a novel molecular target with translational potential in diverse human diseases. Txnip has several established cellular actions including binding to thioredoxin, a scavenger of reactive oxygen species (ROS). It has been long recognized from in vitro evidence that Txnip forms a disulfide bridge through cysteine 247 (C247) with reduced thioredoxin to inhibit the anti-oxidative properties of thioredoxin. However, the physiological significance of the Txnip-thioredoxin interaction remains largely undefined in vivo.OBJECTIVE: A single mutation of Txnip, C247S, abolishes the binding of Txnip with thioredoxin. Using a conditional and inducible approach with a mouse model of a mutant Txnip that does not bind thioredoxin, we tested whether the interaction of thioredoxin with Txnip is required for Txnip's pro-oxidative or cytotoxic effects in the heart.
METHODS AND RESULTS: Overexpression of Txnip C247S in cells resulted in a reduction in ROS, due to an inability to inhibit thioredoxin. Hypoxia (1% O2, 24 h)-induced killing effects of Txnip were decreased by lower levels of cellular ROS in Txnip C247S-expressing cells compared with wild-type Txnip-expressing cells. Then, myocardial ischemic injuries were assessed in the animal model. Cardiomyocyte-specific Txnip C247S knock-in mice had better survival with smaller infarct size following MI compared to control animals. The absence of Txnip's inhibition of thioredoxin promoted mitochondrial anti-oxidative capacities in cardiomyocytes, thereby protecting the heart from oxidative damage induced by myocardial infarction. Furthermore, an unbiased RNA sequencing screen identified that hypoxia-inducible factor 1 signaling pathway was involved in Txnip C247S-mediated cardioprotective mechanisms.
CONCLUSION: Txnip is a cysteine-containing redox protein that robustly regulates the thioredoxin system via a disulfide bond-switching mechanism in adult cardiomyocytes. Our results provide the direct in vivo evidence that regulation of redox state by Txnip is a crucial component for myocardial homeostasis under ischemic stress.

Keywords:  Cell death; Metabolism; Mitochondria; ROS

DOI:  https://doi.org/10.1016/j.yjmcc.2021.02.013
Basic Res Cardiol. 2021 Mar 06. 116(1): 15

SAIL: a new conserved anti-fibrotic lncRNA in the heart.

Shenjian Luo, Mingyu Zhang, Hao Wu, Xin Ding, Danyang Li, Xue Dong, Xiaoxi Hu, Shuang Su, Wendi Shang, Jiaxu Wu, Hongwen Xiao, Wanqi Yang, Qi Zhang, Jifan Zhang, Yanjie Lu, Zhenwei Pan.

  Long non-coding RNAs (lncRNAs) account for a large proportion of genomic transcripts and are critical regulators in various cardiac diseases. Though lncRNAs have been reported to participate in the process of diverse cardiac diseases, the contribution of lncRNAs in cardiac fibrosis remains to be fully elucidated. Here, we identified a novel anti-fibrotic lncRNA, SAIL (scaffold attachment factor B interacting lncRNA). SAIL was reduced in cardiac fibrotic tissue and activated cardiac fibroblasts. Gain- and loss-of-function studies showed that knockdown of SAIL promoted proliferation and collagen production of cardiac fibroblasts with or without TGF-β1 (transforming growth factor beta1) treatment, while overexpression of SAIL did the opposite. In mouse cardiac fibrosis induced by myocardial infarction, knockdown of SAIL exacerbated, whereas overexpression of SAIL alleviated cardiac fibrosis. Mechanically, SAIL inhibited the fibrotic process by directly binding with SAFB via 23 conserved nucleotide sequences, which in turn blocked the access of SAFB to RNA pol II (RNA polymerase II) and reduced the transcription of fibrosis-related genes. Intriguingly, the human conserved fragment of SAIL (hSAIL) significantly suppressed the proliferation and collagen production of human cardiac fibroblasts. Our findings demonstrate that SAIL regulates cardiac fibrosis by regulating SAFB-mediated transcription of fibrotic related genes. Both SAIL and SAFB hold the potential to become novel therapeutic targets for cardiac fibrosis.

Keywords:  Cardiac fibrosis; RNA pol II; RNA-seq; SAFB; lncRNA

DOI:  https://doi.org/10.1007/s00395-021-00854-y
J Nanobiotechnology. 2021 Feb 27. 19(1): 61

Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p.

Wenwu Zhu, Ling Sun, Pengcheng Zhao, Yaowu Liu, Jian Zhang, Yuelin Zhang, Yimei Hong, Yeqian Zhu, Yao Lu, Wei Zhao, Xinguang Chen, Fengxiang Zhang.

  BACKGROUND: Exosome transplantation is a promising cell-free therapeutic approach for the treatment of ischemic heart disease. The purpose of this study was to explore whether exosomes derived from Macrophage migration inhibitory factor (MIF) engineered umbilical cord MSCs (ucMSCs) exhibit superior cardioprotective effects in a rat model of AMI and reveal the mechanisms underlying it.RESULTS: Exosomes isolated from ucMSCs (MSC-Exo), MIF engineered ucMSCs (MIF-Exo) and MIF downregulated ucMSCs (siMIF-Exo) were used to investigate cellular protective function in human umbilical vein endothelial cells (HUVECs) and H9C2 cardiomyocytes under hypoxia and serum deprivation (H/SD) and infarcted hearts in rats. Compared with MSC-Exo and siMIF-Exo, MIF-Exo significantly enhanced proliferation, migration, and angiogenesis of HUVECs and inhibited H9C2 cardiomyocyte apoptosis under H/SD in vitro. MIF-Exo also significantly inhibited cardiomyocyte apoptosis, reduced fibrotic area, and improved cardiac function as measured by echocardiography in infarcted rats in vivo. Exosomal miRNAs sequencing and qRT-PCR confirmed miRNA-133a-3p significantly increased in MIF-Exo. The biological effects of HUVECs and H9C2 cardiomyocytes were attenuated with incubation of MIF-Exo and miR-133a-3p inhibitors. These effects were accentuated with incubation of siMIF-Exo and miR-133a-3p mimics that increased the phosphorylation of AKT protein in these cells.
CONCLUSION: MIF-Exo can provide cardioprotective effects by promoting angiogenesis, inhibiting apoptosis, reducing fibrosis, and preserving heart function in vitro and in vivo. The mechanism in the biological activities of MIF-Exo involves miR-133a-3p and the downstream AKT signaling pathway.

Keywords:  Exosomes; Macrophage migration inhibitory factor; MiR-133a-3p; Myocardial infarction; UcMSCs

DOI:  https://doi.org/10.1186/s12951-021-00808-5
Redox Biol. 2021 Feb 22. pii: S2213-2317(21)00058-6. [Epub ahead of print]41 101910

The lncRNA Malat1 regulates microvascular function after myocardial infarction in mice via miR-26b-5p/Mfn1 axis-mediated mitochondrial dynamics.

Yuqiong Chen, Su Li, Yan Zhang, Mengshen Wang, Xinyan Li, Shuang Liu, Dengyue Xu, Yandong Bao, Pengyu Jia, Nan Wu, Yao Lu, Dalin Jia.

  RATIONALE: Myocardial infarction (MI) is a leading cause of cardiovascular mortality globally. The improvement of microvascular function is critical for cardiac repair after MI. Evidence now points to long non-coding RNAs (lncRNAs) as key regulators of cardiac remodelling processes. The lncRNA Malat1 is involved in the development and progression of multiple cardiac diseases. Studies have shown that Malat1 is closely related to the regulation of endothelial cell regeneration. However, the potential molecular mechanisms of Malat1 in repairing cardiac microvascular dysfunction after MI remain unreported.METHODS AND RESULTS: The present study found that Malat1 is upregulated in the border zone of infarction in mouse hearts, as well as in isolated cardiac microvascular endothelial cells (CMECs). Targeted knockdown of Malat1 in endothelial cells exacerbated oxidative stress, attenuated angiogenesis and microvascular perfusion, and as a result decreased cardiac function in MI mice. Further studies showed that silencing Malat1 obviously inhibited CMEC proliferation, migration and tube formation, which was at least in part attributed to disturbed mitochondrial dynamics and activation of the mitochondrial apoptosis pathway. Moreover, bioinformatic analyses, luciferase assays and pull-down assays indicated that Malat1 acted as a competing endogenous RNA (ceRNA) for miR-26b-5p and formed a signalling axis with Mfn1 to regulate mitochondrial dynamics and endothelial functions. Overexpression of Mfn1 markedly reversed the microvascular dysfunction and CMEC injuries that were aggravated by silencing Malat1 via inhibition of excessive mitochondrial fragments and mitochondria-dependent apoptosis.
CONCLUSIONS: The present study elucidated the functions and mechanisms of Malat1 in cardiac microcirculation repair after MI. The underlying mechanisms of the effects of Malat1 could be attributed to its blocking effects on miR-26b-5p/Mfn1 pathway-mediated mitochondrial dynamics and apoptosis.

Keywords:  Cardiac microvascular dysfunction; Malat1; Mfn1; Myocardial infarction; miR-26b-5p

DOI:  https://doi.org/10.1016/j.redox.2021.101910
Front Physiol. 2021 ;12 593862

Impact of PCSK9 on CTRP9-Induced Metabolic Effects in Adult Rat Cardiomyocytes.

Susanne Rohrbach, Ling Li, Tatyana Novoyatleva, Bernd Niemann, Fabienne Knapp, Nicole Molenda, Rainer Schulz.

  The adipocytokine adiponectin and its structural homologs, the C1q/TNF-related proteins (CTRPs), increase insulin sensitivity, fatty acid oxidation and mitochondrial biogenesis. Adiponectin- and CTRP-induced signal transduction has been described to involve the adiponectin receptors and a number of co-receptors including the Low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is another target of the proprotein convertase subtilisin/kexin-9 (PCSK9) in addition to the LDL-receptor (LDL-R). Here, we investigated the influence of PCSK9 on the metabolic effects of CTRP9, the CTRP with the highest homology to adiponectin. Knockdown of LRP1 in H9C2 cardiomyoblasts blunts the effects of CTRP9 on signal transduction and mitochondrial biogenesis, suggesting its involvement in CTRP9-induced cellular effects. Treatment of adult rat cardiomyocytes with recombinant PCSK9 but not knockdown of endogenous PCSK9 by siRNA results in a strong reduction in LRP1 protein expression and subsequently reduces the mitochondrial biogenic effect of CTRP9. PCSK9 treatment (24 h) blunts the effects of CTRP9-induced signaling cascade activation (AMP-dependent protein kinase, protein kinase B). In addition, the stimulating effects of CTRP9 on cardiomyocyte mitochondrial biogenesis and glucose metabolism (GLUT-4 translocation, glucose uptake) are largely blunted. Basal fatty acid (FA) uptake is strongly reduced by exogenous PCSK9, although protein expression of the PCSK9 target CD36, the key regulator of FA transport in cardiomyocytes, is not altered. In addition, only minor effects of PCSK9 were observed on CTRP9-induced FA uptake or the expression of genes involved in FA metabolism or uptake. Finally, this CTRP9-induced increase in CD36 expression occurs independent from LRP1 and LDL-R. In conclusion, PCSK9 treatment influences LRP1-mediated signaling pathways in cardiomyocytes. Thus, therapeutic PCSK9 inhibition may provide an additional benefit through stimulation of glucose metabolism and mitochondrial biogenesis in addition to the known lipid-lowering effects. This could be an important beneficial side effect in situations with impaired mitochondrial function and reduced metabolic flexibility thereby influencing cardiac function.

Keywords:  LRP1; PCSK9; adiponectin; cardiomyocyte; metabolism; mitochondria

DOI:  https://doi.org/10.3389/fphys.2021.593862
iScience. 2021 Feb 19. 24(2): 102124

Activation of amino acid metabolic program in cardiac HIF1-alpha-deficient mice.

Ivan Menendez-Montes, Beatriz Escobar, Manuel J Gomez, Teresa Albendea-Gomez, Beatriz Palacios, Elena Bonzon-Kulichenko, Jose Luis Izquierdo-Garcia, Ana Vanessa Alonso, Alessia Ferrarini, Luis Jesus Jimenez-Borreguero, Jesus Ruiz-Cabello, Jesus Vázquez, Silvia Martin-Puig.

  HIF1-alpha expression defines metabolic compartments in the developing heart, promoting glycolytic program in the compact myocardium and mitochondrial enrichment in the trabeculae. Nonetheless, its role in cardiogenesis is debated. To assess the importance of HIF1-alpha during heart development and the influence of glycolysis in ventricular chamber formation, herein we generated conditional knockout models of Hif1a in Nkx2.5 cardiac progenitors and cardiomyocytes. Deletion of Hif1a impairs embryonic glycolysis without influencing cardiomyocyte proliferation and results in increased mitochondrial number and transient activation of amino acid catabolism together with HIF2α and ATF4 upregulation by E12.5. Hif1a mutants display normal fatty acid oxidation program and do not show cardiac dysfunction in the adulthood. Our results demonstrate that cardiac HIF1 signaling and glycolysis are dispensable for mouse heart development and reveal the metabolic flexibility of the embryonic myocardium to consume amino acids, raising the potential use of alternative metabolic substrates as therapeutic interventions during ischemic events.

Keywords:  Animal Physiology; Biological Sciences; Cellular Physiology; Developmental Biology

DOI:  https://doi.org/10.1016/j.isci.2021.102124
Eur J Pharmacol. 2021 Feb 25. pii: S0014-2999(21)00140-0. [Epub ahead of print] 173987

Effects of Hsp90 inhibitor on the RIP1-RIP3-MLKL pathway during the development of heart failure in mice.

Tetsuro Marunouchi, Chiharu Nishiumi, Saki Iinuma, Emi Yano, Kouichi Tanonaka.

  Necroptosis is a programmed form of necrotic cell death. Necroptosis is regulated by the necroptosis-regulating proteins including receptor-interacting protein (RIP) 1, RIP3, and mixed lineage kinase domain-like (MLKL), the activities of which are modulated by the molecular chaperone heat-shock protein (Hsp) 90. Presently, to clarify the relationship between Hsp90 and necroptotic pathway proteins, RIP1, RIP3, and MLKL in the development of heart failure, we examined the effects of Hsp90 inhibitor treatment on the RIP1-RIP3-MLKL pathway in mice following transverse aortic constriction (TAC). In this study, TAC mice showed typical signs of heart failure at the 8th week after the operation. In the failing heart, the levels of these regulatory proteins and those of their phosphorylated forms were increased, suggesting that necroptosis contributed to the development of heart failure in the TAC mice. The increases in RIP1, RIP3, and MLKL after TAC were reversed by the administration of an Hsp90 inhibitor. Furthermore, the rise in the phosphorylation levels of these 3 proteins were attenuated by the Hsp90 inhibitor. Concomitantly, cardiac functions were preserved. We also found that exposure of cultured adult mouse cardiomyocytes to the Hsp90 inhibitor attenuated necrotic cell death induced by tumor necrosis factor-α via suppression of RIP1, RIP3, and MLKL activation in in vitro experiments. Taken together, our findings suggest that inhibition of Hsp90 should have therapeutic effects by reducing the activation of RIP1-RIP3-MLKL pathway in the hypertrophied heart and thus could be a new therapeutic strategy for chronic heart failure.

Keywords:  Heart failure; Hsp90; MLKL; RIP1; RIP3

DOI:  https://doi.org/10.1016/j.ejphar.2021.173987
Transl Res. 2021 Feb 27. pii: S1931-5244(21)00048-7. [Epub ahead of print]

Toll-like receptor 2 signaling deficiency in cardiac cells ameliorates Ang II-induced cardiac inflammation and remodeling.

Shiju Ye, Ke Lin, Gaojun Wu, Ming-Jiang Xu, Peiren Shan, Weijian Huang, Yi Wang, Guang Liang.

  Activation of the innate immune system represents a vital step in inflammation during cardiac remodeling induced by the angiotensin II (Ang II). This study aimed to explore the role of Toll-like receptors 2 (TLR2) in Ang II-induced cardiac remodeling. We investigated the effect of TLR2 deficiency on Ang II-induced cardiac remodeling by utilizing TLR2 knockout mice, bone marrow transplantation models, and H9C2 cells. Though TLR2 deficiency had no effect on body weight change, cardiac Ang II content and blood pressure, it significantly ameliorated cardiac hypertrophy, fibrosis and inflammation, as well as improved heart function. Further bone marrow transplantation studies showed that TLR2-deficiency in cardiac cells but not bone marrow-derived cells prevented Ang II-induced cardiac remodeling and cardiac dysfunction. The underlying mechanism may involve increased TLR2-MyD88 interaction. Further in vitro studies in Ang II-treated H9C2 cells showed that TLR2 knockdown by siRNA significantly decreased Ang II-induced cell hypertrophy, fibrosis and inflammation. Moreover, Ang II significantly increased TLR2-MyD88 interaction in H9C2 cells in a TLR4-independent manner. TLR2 deficiency in cardiac cells prevents Ang II-induced cardiac remodeling, inflammation and dysfunction through reducing the formation of TLR2-MyD88 complexes. Inhibition of TLR2 pathway may be a therapeutic strategy of hypertensive heart failure.

Keywords:  TLR2; angiotensin II; heart failure; inflammation, cardiomyocyte

DOI:  https://doi.org/10.1016/j.trsl.2021.02.011
Antioxidants (Basel). 2021 Feb 24. pii: 338. [Epub ahead of print]10(3):

Sirt1 and Sirt3 Activation Improved Cardiac Function of Diabetic Rats via Modulation of Mitochondrial Function.

Bugga Paramesha, Mohammed Soheb Anwar, Himanshu Meghwani, Subir Kumar Maulik, Sudheer Kumar Arava, Sanjay K Banerjee.

  In the present study, we aimed to evaluate the effect of Sirt1, Sirt3 and combined activation in high fructose diet-induced insulin resistance rat heart and assessed the cardiac function focusing on mitochondrial health and function. We administered the Sirt1 activator; SRT1720 (5 mg/kg, i.p.), Sirt3 activator; Oroxylin-A (10 mg/kg i.p.) and the combination; SRT1720 + Oroxylin-A (5 mg/kg and 10 mg/kg i.p.) daily from 12th week to 20th weeks of study. We observed significant perturbations of most of the cardiac structural and functional parameters in high fructose diet-fed animals. Administration of SRT1720 and Oroxylin-A improved perturbed cardiac structural and functional parameters by decreasing insulin resistance, oxidative stress, and improving mitochondrial function by enhancing mitochondrial biogenesis, OXPHOS expression and activity in high fructose diet-induced insulin-resistant rats. However, we could not observe the synergistic effect of SRT1720 and Oroxylin-A combination. Similar to in-vivo study, perturbed mitochondrial function and oxidative stress observed in insulin-resistant H9c2 cells were improved after activation of Sirt1 and Sirt3. We observed that Sirt1 activation enhances Sirt3 expression and mitochondrial biogenesis, and the opposite effects were observed after Sirt1 inhibition in cardiomyoblast cells. Taken together our results conclude that activation of Sirt1 alone could be a potential therapeutic target for diabetes-associated cardiovascular complications.

Keywords:  OXPHOS; insulin resistance; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3390/antiox10030338
Int J Mol Sci. 2021 Feb 24. pii: 2245. [Epub ahead of print]22(5):

Selective Cardiomyocyte Oxidative Stress Leads to Bystander Senescence of Cardiac Stromal Cells.

Hélène Martini, Lise Lefevre, Sylvain Sayir, Romain Itier, Damien Maggiorani, Marianne Dutaur, Dimitri J Marsal, Jérôme Roncalli, Nathalie Pizzinat, Daniel Cussac, Angelo Parini, Jeanne Mialet-Perez, Victorine Douin-Echinard.

  Accumulation of senescent cells in tissues during normal or accelerated aging has been shown to be detrimental and to favor the outcomes of age-related diseases such as heart failure (HF). We have previously shown that oxidative stress dependent on monoamine oxidase A (MAOA) activity in cardiomyocytes promotes mitochondrial damage, the formation of telomere-associated foci, senescence markers, and triggers systolic cardiac dysfunction in a model of transgenic mice overexpressing MAOA in cardiomyocytes (Tg MAOA). However, the impact of cardiomyocyte oxidative stress on the cardiac microenvironment in vivo is still unclear. Our results showed that systolic cardiac dysfunction in Tg MAOA mice was strongly correlated with oxidative stress induced premature senescence of cardiac stromal cells favoring the recruitment of CCR2+ monocytes and the installation of cardiac inflammation. Understanding the interplay between oxidative stress induced premature senescence and accelerated cardiac dysfunction will help to define new molecular pathways at the crossroad between cardiac dysfunction and accelerated aging, which could contribute to the increased susceptibility of the elderly to HF.

Keywords:  CCR2+ Macrophages; SASP; cardiac mesenchymal stromal cells; monoamine oxidase A; oxidative stress; stress-induced premature senescence

DOI:  https://doi.org/10.3390/ijms22052245
J Cardiovasc Pharmacol. 2021 Mar 01. 77(3): 378-385

Pharmacological Pre- and Postconditioning With Levosimendan Protect H9c2 Cardiomyoblasts From Anoxia/Reoxygenation-induced Cell Death via PI3K/Akt Signaling.

Antje Schauer, Peggy Barthel, Volker Adams, Axel Linke, David M Poitz, Christof Weinbrenner.

ABSTRACT: The calcium sensitizer levosimendan is indicated for the hemodynamic stabilization of patients with acutely decompensated heart failure and has been shown to be protective against reperfusion injury after myocardial infarction. However, affected forms of cell death and underlying signaling pathways remain controversial. Therefore, the aim of this study was to examine the influence of levosimendan preconditioning and postconditioning on anoxia/reoxygenation-induced apoptosis, necrosis, and autophagy in H9c2 myoblasts. To mimic conditions of myocardial ischemia/reperfusion, rat cardiac H9c2 myoblasts were exposed to anoxia/starvation, followed by reoxygenation/refeeding. Apoptosis, necrosis, autophagy, cell viability, survival signaling, and mitochondrial permeability transition pore (mPTP) opening were measured. Both, pharmacological preconditioning and postconditioning with levosimendan were capable to reduce apoptosis as well as necrosis in stressed H9c2 cells. However, preconditioning showed to have the stronger impact compared with postconditioning. Moreover, levosimendan preconditioning increased autophagy, suggesting enhanced repair processes initiated by the early presence of the drug. Underlying mechanisms differ between both interventions: Although both are associated with PI3/Akt activation and reduced mPTP opening, only postconditioning but not preconditioning depended on mKATP activation. This variation might indicate that a pharmacological treatment after the onset of reoxygenation at least in part directly addresses mitochondrial structures for protection. In conclusion, we demonstrate that both pharmacological preconditioning and postconditioning with levosimendan protect anoxia/reoxygenation-stressed cells but differ in the underlying mechanisms. These results are decisive to obtain more insights into the beneficial effects of levosimendan in the treatment of reperfusion-mediated damage.

DOI: https://doi.org/10.1097/FJC.0000000000000969
Can J Physiol Pharmacol. 2021 Feb 27.

Rosuvastatin corrects oxidative stress and inflammation induced by LPS to attenuate cardiac injury by inhibiting the NLRP3/TLR4 pathway.

Guocheng Ren, Qiujie Zhou, Meili Lu, Hongxin Wang.

The aim of the current study was to evaluate whether rosuvastatin was effective in attenuating cardiac injury in lipopolysaccharide(LPS)-challenged mice and H9C2 cells and identify the underlying mechanisms, focusing on the NLRP3/TLR4 pathway. Cardiac injury, cardiac function, apoptosis, oxidative stress, inflammatory response and the NLRP3/TLR4 pathway were evaluated in both in vivo and in vitro studies. LPS-induced cardiomyocytes injury was markedly attenuated by rosuvastatin treatment. Apoptosis was clearly ameliorated in myocardial tissue and H9C2 cells cotreated with rosuvastatin. In addition, excessive oxidative stress was present, as indicated by increases in MDA content, NADPH activity and ROS production and decreased SOD activity after LPS challenge. Rosuvastatin improved all the indicators of oxidative stress, with a similar effect to NAC(ROS scavenger). Notably, LPS-exposed H9C2 cells and mice showed significant NLRP3 and TLR4/NF-κB pathway activation. Administration of rosuvastatin reduced the increases in expression of NLRP3, ASC, pro-caspase-1, TLR4, and p65 and decreased the contents of TNF-α, IL-1β, IL-18 and IL-6, with a similar effect as MCC950 (NLRP3 inhibitor). In conclusion, inhibition of the inflammatory response and oxidative stress contributes to cardioprotection of rosuvastatin on cardiac injury induced by LPS, and the effect of rosuvastatin was achieved by inactivation of the NF-κB/NLRP3 pathway.

DOI: https://doi.org/10.1139/cjpp-2020-0321
Life Sci. 2021 Feb 27. pii: S0024-3205(21)00224-1. [Epub ahead of print]273 119239

Qiliqiangxin alleviates Ang II-induced CMECs apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis.

Fuhai Li, Jingfeng Wang, Yu Song, Dongli Shen, Yongchao Zhao, Chaofu Li, Mingqiang Fu, Yanyan Wang, Baozheng Qi, Xueting Han, Aijun Sun, Jingmin Zhou, Junbo Ge.

  Our previous work revealed the protective effect of Qiliqiangxin (QLQX) on cardiac microvascular endothelial cells (CMECs), but the underlying mechanisms remain unclear. We aimed to investigate whether QLQX exerts its protective effect against high-concentration angiotensin II (Ang II)-induced CMEC apoptosis through the autophagy machinery. CMECs were cultured in high-concentration Ang II (1 μM) medium in the presence or absence of QLQX for 48 h. We found that QLQX obviously inhibited Ang II-triggered autophagosome synthesis and apoptosis in cultured CMECs. QLQX-mediated protection against Ang II-induced CMEC apoptosis was reversed by the autophagy activator rapamycin. Specifically, deletion of ATG7 in cultured CMECs indicated a detrimental role of autophagy in Ang II-induced CMEC apoptosis. QLQX reversed Ang II-mediated ErbB2 phosphorylation impairment. Furthermore, inhibition of ErbB2 phosphorylation with lapatinib in CMECs revealed that QLQX-induced downregulation of Ang II-activated autophagy and apoptosis was ErbB2 phosphorylation-dependent via the AKT-FoxO3a axis. Activation of ErbB2 phosphorylation by Neuregulin-1β achieved a similar CMEC-protective effect as QLQX in high-concentration Ang II medium, and this effect was also abolished by autophagy activation. These results show that the CMEC-protective effect of QLQX under high-concentration Ang II conditions could be partly attributable to QLQX-mediated ErbB2 phosphorylation-dependent downregulation of autophagy via the AKT-FoxO3a axis.

Keywords:  Apoptosis; Autophagy; Cardiac microvascular endothelial cells; ErbB2; Qiliqiangxin

DOI:  https://doi.org/10.1016/j.lfs.2021.119239
Am J Physiol Heart Circ Physiol. 2021 Mar 05.

The peroxisomal enzyme, FAR1, is induced during ER stress in an ATF6-dependent manner in cardiac myocytes.

Kayleigh G Marsh, Adrian Arrieta, Donna J Thuerauf, Erik A Blackwood, Lauren MacDonnell, Christopher C Glembotski.

  While peroxisomes have been extensively studied in other cell types, their presence and function have gone virtually unexamined in cardiac myocytes. Here, in neonatal rat ventricular myocytes (NRVM) we showed that several known peroxisomal proteins co-localize to punctate structures with a morphology typical of peroxisomes. Surprisingly, we found that the peroxisomal protein, fatty acyl-CoA reductase 1 (FAR1), was upregulated by chemical and pathophysiological ER stress induced by tunicamycin (TM) and simulated ischemia/reperfusion (sI/R), respectively. Moreover, FAR1 induction in NRVM was mediated by the ER stress-sensor, activating transcription factor 6 (ATF6). Functionally, FAR1 knockdown reduced myocyte death during oxidative stress induced by either sI/R or hydrogen peroxide (H2O2). Thus, Far1 is an ER stress-inducible gene, which encodes a protein that localizes to peroxisomes of cardiac myocytes, where it reduces myocyte viability during oxidative stress. Since FAR1 is critical for plasmalogen synthesis, these results imply that plasmalogens may exert maladaptive effects on the viability of myocytes exposed to oxidative stress.

Keywords:  ATF6; Cardiac Myocyte; ER Stress; Peroxisome

DOI:  https://doi.org/10.1152/ajpheart.00999.2020
Cardiovasc Drugs Ther. 2021 Mar 04.

Vitamin D3 Supplementation Alleviates Left Ventricular Dysfunction in a Mouse Model of Diet-Induced Type 2 Diabetes: Potential Involvement of Cardiac Lipotoxicity Modulation.

Clothilde Philouze, Jean-Charles Martin, Catherine Riva, Alexandra Marziou, Catherine Defoort, Charlène Couturier, Thierry Berton, Julien Astier, Bernard Jover, Nathalie Gayrard, Cyril Reboul, Sandrine Gayrard, Jean-François Landrier, Philippe Obert.

  PURPOSE: To evaluate the effectiveness of vitamin D3 supplementation, in secondary prevention, on cardiac remodeling and function, as well as lipid profile, in a mouse model of diet-induced type 2 diabetes.METHODS: Mice were fed a high fat and sucrose diet for 10 weeks. Afterward, diet was maintained for 15 more weeks and two groups were formed, with and without cholecalciferol supplementation. A control group was fed with normal chow. Glucose homeostasis and cardiac function were assessed at baseline and at the 10th and 24th weeks. Animals were killed at the 10th and 25th weeks for plasma and cardiac sample analysis. Cardiac lipid profile was characterized by LC-MS/MS.
RESULTS: After 10 weeks of diet, mice exhibited pre-diabetes, mild left ventricle hypertrophy, and impaired longitudinal strain, but preserved myocardial circumferential as well as global diastolic and systolic cardiac function. After 15 more weeks of diet, animals presented with well-established type 2 diabetes, pathological cardiac hypertrophy, and impaired regional myocardial function. Cholecalciferol supplementation had no effect on glucose homeostasis but improved cardiac remodeling and regional myocardial function. After 25 weeks, non-supplemented mice exhibited increased myocardial levels of ceramides and diacylglycerol, both of which were normalized by vitamin D3 supplementation.
CONCLUSION: This work brought to light the beneficial effects of cholecalciferol supplementation, in secondary prevention, on cardiac remodeling and function in a mouse model of diet-induced type 2 diabetes. Those cardioprotective effects may be, at least in part, attributed to the modulation of myocardial levels of lipotoxic species by vitamin D.

Keywords:  Cardiac lipotoxicity; Regional myocardial function; Type 2 diabetes; Vitamin D

DOI:  https://doi.org/10.1007/s10557-021-07143-9
Inflammation. 2021 Mar 04.

LncRNA HOTAIR Promotes LPS-Induced Inflammation and Apoptosis of Cardiomyocytes via Lin28-Mediated PDCD4 Stability.

Shu-Yuan Ni, Wen-Ting Xu, Guang-Yuan Liao, Yin-Ling Wang, Jing Li.

  Sepsis is one of the primary causes of death in intensive care units. Recently, increasing evidence has identified lncRNA HOTAIR is involved in septic cardiomyopathy. However, the potential mechanism underlying HOTAIR on septic cardiomyopathy is still unknown. H9C2 cells were treated with lipopolysaccharide (LPS) after transfection with sh-HOTAIR, sh-Lin28, pcDNA3.1-HOTAIR, and pcDNA3.1-PDCD4. qRT-PCR was used to examine the level of HOTAIR, Lin28, PDCD4, and sepsis-related inflammatory cytokines. Flow cytometric analysis was applied to detect cell apoptosis. The interaction between Lin28 and HOTAIR or PDCD4 was verified by RNA pull-down and RIP assay. HOTAIR levels were interfered by AAV9-sh-HOTAIR in LPS-induced septic cardiomyopathy mice. ELISA analysis was used to evaluate TNF-α, IL-6, and IL-1β level. Western blot was used to detect the expression of LIN28 and PDCD4 in mouse cardiomyocytes. Echocardiography was used to evaluate the cardiac function. In our study, knockdown of HOTAIR inhibited LPS-induced inflammation and H9C2 cells apoptosis. HOTAIR promoted LPS-induced inflammatory response and apoptosis of H9C2 cells by enhancing PDCD4 stability. RNA pull-down and RIP assay exhibited that Lin28, a highly conserved RNA-binding protein, was combined with HOTAIR and PDCD4. The in vivo experiments verified that the HOTAIR knockdown alleviated the cardiac function injury and secretion of inflammatory factors caused by sepsis. In conclusion, our findings supported that the HOTAIR/Lin28/PDCD4 axis serves as a critical regulator of sepsis, which may open a new direction for the development of sepsis therapeutic.

Keywords:  Apoptosis; Cardiomyocytes; HOTAIR; Lin28; PDCD4; Sepsis

DOI:  https://doi.org/10.1007/s10753-021-01431-0
Curr Cardiol Rep. 2021 Mar 02. 23(4): 29

A Roadmap to Heart Regeneration Through Conserved Mechanisms in Zebrafish and Mammals.

Kyla D Brezitski, Alexander W Goff, Paige DeBenedittis, Ravi Karra.

  PURPOSE OF REVIEW: The replenishment of lost or damaged myocardium has the potential to reverse heart failure, making heart regeneration a goal for cardiovascular medicine. Unlike adult mammals, injury to the zebrafish or neonatal mouse heart induces a robust regenerative program with minimal scarring. Recent insights into the cellular and molecular mechanisms of heart regeneration suggest that the machinery for regeneration is conserved from zebrafish to mammals. Here, we will review conserved mechanisms of heart regeneration and their translational implications.RECENT FINDINGS: Based on studies in zebrafish and neonatal mice, cardiomyocyte proliferation has emerged as a primary strategy for effecting regeneration in the adult mammalian heart. Recent work has revealed pathways for stimulating cardiomyocyte cell cycle reentry; potential developmental barriers for cardiomyocyte proliferation; and the critical role of additional cell types to support heart regeneration. Studies in zebrafish and neonatal mice have established a template for heart regeneration. Continued comparative work has the potential to inform the translation of regenerative biology into therapeutics.

Keywords:  Cardiomyocyte proliferation; Heart failure; Regeneration

DOI:  https://doi.org/10.1007/s11886-021-01459-6
Circulation. 2021 Mar 05.

Suppression of Myocardial HIF-1α Compromises Metabolic Adaptation and Impairs Cardiac Function in Patients with Cyanotic Congenital Heart Disease During Puberty.

Yiwei Liu, Qipeng Luo, Zhanhao Su, Junyue Xing, Jinlin Wu, Li Xiang, Yuan Huang, Haizhou Pan, Xie Wu, Xiaoling Zhang, Jun Li, Fuxia Yan, Hao Zhang.

  Background: Cyanotic congenital heart disease (CCHD) is a complex pathophysiological condition involving systemic chronic hypoxia (CH). Some CCHD patients are unoperated due to various reasons and remain chronically hypoxic throughout their lives, which heightens the risk of heart failure as they age. Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-α (HIF-1α). This study aims to determine the effect of CH on cardiac metabolism and function in CCHD patients and its association with age. The role of HIF-1α in this process was investigated and potential therapeutic targets were explored. Methods: CCHD patients (n = 25) were evaluated for cardiac metabolism and function using positron-emission tomography/computed tomography and magnetic resonance imaging. Heart tissue samples were subjected to metabolomic and protein analyses. CH rodent models were generated to enable continuous observation of changes in cardiac metabolism and function. The role of HIF-1α in cardiac metabolic adaptation to CH was investigated using genetically modified animals and isotope-labeled metabolomic-pathway tracing studies. Results: Prepubertal CCHD patients had glucose-dominant cardiac metabolism and normal cardiac function. By comparison, among patients who had entered puberty, the levels of myocardial glucose uptake and glycolytic intermediates were significantly decreased, but fatty acids were significantly increased, along with decreased left-ventricular ejection fraction. These clinical phenotypes were replicated in CH rodent models. In CCHD patients and animals exposed to CH, myocardial HIF-1α was upregulated prior to puberty, but was significantly downregulated during puberty. In cardiomyocyte-specific Hif-1α-knockout mice, CH failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance (IR) during puberty suppressed myocardial HIF-1α and was responsible for cardiac metabolic maladaptation in animals exposed to CH. Pioglitazone significantly reduced myocardial IR, restored glucose metabolism, and improved cardiac function in pubertal CH animals. Conclusions: In CCHD patients, maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. HIF-1α was identified as the key regulator of cardiac metabolic adaptation in animals exposed to CH, and pubertal IR could suppress its expression. Pioglitazone administration during puberty might help improve cardiac function in CCHD patients.

Keywords:  Cyanotic congenital heart disease; chronic hypoxia; metabolic adaptation; pioglitazone

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.120.051937
Int J Mol Sci. 2021 Feb 13. pii: 1861. [Epub ahead of print]22(4):

The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis.

Jemima Seidenberg, Mara Stellato, Amela Hukara, Burkhard Ludewig, Karin Klingel, Oliver Distler, Przemysław Błyszczuk, Gabriela Kania.

  BACKGROUND: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown.METHODS AND RESULTS: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis.
CONCLUSION: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

Keywords:  Fos-related antigen 2; autophagy; cardiac fibroblasts; cardiac fibrosis; cardiac hypertrophy

DOI:  https://doi.org/10.3390/ijms22041861
Mol Med Rep. 2021 Apr;23(4): 1-8

Hyperoside protects cardiomyocytes against hypoxia‑induced injury via upregulation of microRNA‑138.

Siyi He, Xiaoqiang Yin, Fan Wu, Shaojie Zeng, Feng Gao, Mei Xin, Jian Wang, Jie Chen, Le Zhang, Jinbao Zhang.

Following hypoxia, cardiomyocytes are susceptible to damage, against which microRNA (miR)‑138 may act protectively. Hyperoside (Hyp) is a Chinese herbal medicine with multiple biological functions that serve an important role in cardiovascular disease. The aim of the present study was to investigate the role of Hyp in hypoxic cardiomyocytes and its effect on miR‑138. A hypoxia model was established in both H9C2 cells and C57BL/6 mice, which were stimulated by Hyp. The expression levels of miR‑138 were increased in the hypoxic myocardium in the presence of Hyp at concentrations of >50 µmol/l in vivo and >50 mg/kg in vitro. Using Cell Counting Kit‑8 and 5‑ethynyl‑2'‑deoxyuridine assays, it was observed that Hyp improved hypoxia‑induced impairment of cell proliferation. Cell apoptosis was evaluated by flow cytometry and a TUNEL assay. The number of apoptotic cells in the Hyp group was lower than that in the control group. As markers of myocardial injury, the levels of lactate dehydrogenase, creatine kinase‑myocardial band isoenzyme and malondialdehyde were decreased in the Hyp group compared with the control group, whereas the levels of superoxide dismutase were increased. A marked decrease in the levels of cleaved caspase‑3 and cleaved poly(ADP) ribose polymerase and a marked increase in expression levels of Bcl‑2 were observed in the presence of Hyp. However, miR‑138 inhibition by antagomir attenuated the protective effects of Hyp. Furthermore, Hyp treatment was associated with marked downregulation of mixed lineage kinase 3 and lipocalin‑2, but not pyruvate dehydrogenase kinase 1, in hypoxic H9C2 cells. These findings demonstrated that Hyp may be beneficial for myocardial cell survival and may alleviate hypoxic injury via upregulation of miR‑138, thereby representing a promising potential strategy for clinical cardioprotection.

DOI: https://doi.org/10.3892/mmr.2021.11925
Front Pharmacol. 2020 ;11 613883

STAT3 Suppresses Cardiomyocytes Apoptosis in CVB3-Induced Myocarditis Via Survivin.

Qiaoyu Wang, Qiongjun Zhu, Qiaofang Ye, Jiajun Wang, Qianqian Dong, Youran Chen, Minna Wang, Yu Fu, Rongzhou Wu, Tingting Wu.

  Background: Viral myocarditis (VMC) is a common inflammatory cardiovascular disease with unclear mechanisms, which mainly affects children and adolescents. Apoptosis is the key to CVB3-induced myocarditis, and blocking this process may be beneficial to the therapy of VMC. Hence, this study aimed to explore the protective function of STAT3 on cardiomyocyte apoptosis of VMC and its underlying mechanisms. Methods and Results: In this research, we confirmed that STAT3 was significantly activated in both animal and cell models of VMC. To further clarify what role did STAT3 play in VMC, AG490, an inhibitor of STAT3, was used to suppress p-STAT3. Our results demonstrated that decreased expression of p-STAT3 caused by AG490 significantly aggravated severity of VMC with elevated myocardial inflammation, deteriorative ventricular systolic function and increased mortality. It suggested that STAT3 plays a protective role in VMC. To further identify the anti-apoptosis impact that activated STAT3 made, we constructed lentivirus to regulate the expression of STAT3 in NMCs. We found that up-regulated activated STAT3 attenuated cardiomyocyte apoptosis, but down-regulated one aggravated that, which verified activated STAT3 played an anti-apoptosis role in VMC. Following that, we explored what elements are involved in the anti-apoptotic mechanism of activated STAT3 by using survivin inhibitor YM155. The result showed the anti-apoptotic effect of activated STAT3 does not work in the case of survivin inhibition. Conclusion: Our findings demonstrated STAT3 by targeting survivin alleviated cardiomyocyte apoptosis in CVB3-induced myocarditis.

Keywords:  apoptosis; coxsackievirus B3; stat3; survivin; viral myocarditis

DOI:  https://doi.org/10.3389/fphar.2020.613883
J Gen Physiol. 2021 Jul 05. pii: e202012770. [Epub ahead of print]153(7):

Cardiac MyBP-C phosphorylation regulates the Frank-Starling relationship in murine hearts.

Laurin M Hanft, Daniel P Fitzsimons, Timothy A Hacker, Richard L Moss, Kerry S McDonald.

The Frank-Starling relationship establishes that elevated end-diastolic volume progressively increases ventricular pressure and stroke volume in healthy hearts. The relationship is modulated by a number of physiological inputs and is often depressed in human heart failure. Emerging evidence suggests that cardiac myosin-binding protein-C (cMyBP-C) contributes to the Frank-Starling relationship. We measured contractile properties at multiple levels of structural organization to determine the role of cMyBP-C and its phosphorylation in regulating (1) the sarcomere length dependence of power in cardiac myofilaments and (2) the Frank-Starling relationship in vivo. We compared transgenic mice expressing wild-type cMyBP-C on the null background, which have ∼50% phosphorylated cMyBP-C (Controls), to transgenic mice lacking cMyBP-C (KO) and to mice expressing cMyBP-C that have serine-273, -282, and -302 mutated to aspartate (cMyBP-C t3SD) or alanine (cMyBP-C t3SA) on the null background to mimic either constitutive PKA phosphorylation or nonphosphorylated cMyBP-C, respectively. We observed a continuum of length dependence of power output in myocyte preparations. Sarcomere length dependence of power progressively increased with a rank ordering of cMyBP-C KO = cMyBP-C t3SA < Control < cMyBP-C t3SD. Length dependence of myofilament power translated, at least in part, to hearts, whereby Frank-Starling relationships were steepest in cMyBP-C t3SD mice. The results support the hypothesis that cMyBP-C and its phosphorylation state tune sarcomere length dependence of myofibrillar power, and these regulatory processes translate across spatial levels of myocardial organization to control beat-to-beat ventricular performance.

DOI: https://doi.org/10.1085/jgp.202012770
Biomedicines. 2021 Feb 18. pii: 204. [Epub ahead of print]9(2):

Role of Adenosine and Purinergic Receptors in Myocardial Infarction: Focus on Different Signal Transduction Pathways.

Maria Cristina Procopio, Rita Lauro, Chiara Nasso, Scipione Carerj, Francesco Squadrito, Alessandra Bitto, Gianluca Di Bella, Antonio Micari, Natasha Irrera, Francesco Costa.

  Myocardial infarction (MI) is a dramatic event often caused by atherosclerotic plaque erosion or rupture and subsequent thrombotic occlusion of a coronary vessel. The low supply of oxygen and nutrients in the infarcted area may result in cardiomyocytes necrosis, replacement of intact myocardium with non-contractile fibrous tissue and left ventricular (LV) function impairment if blood flow is not quickly restored. In this review, we summarized the possible correlation between adenosine system, purinergic system and Wnt/β-catenin pathway and their role in the pathogenesis of cardiac damage following MI. In this context, several pathways are involved and, in particular, the adenosine receptors system shows different interactions between its members and purinergic receptors: their modulation might be effective not only for a normal functional recovery but also for the treatment of heart diseases, thus avoiding fibrosis, reducing infarcted area and limiting scaring. Similarly, it has been shown that Wnt/β catenin pathway is activated following myocardial injury and its unbalanced activation might promote cardiac fibrosis and, consequently, LV systolic function impairment. In this regard, the therapeutic benefits of Wnt inhibitors use were highlighted, thus demonstrating that Wnt/β-catenin pathway might be considered as a therapeutic target to prevent adverse LV remodeling and heart failure following MI.

Keywords:  P2Y12; Wnt; adenosine; fibrosis; myocardial infarction; purinergic receptors; wnt inhibitors; β-catenin

DOI:  https://doi.org/10.3390/biomedicines9020204
Int J Mol Sci. 2021 Feb 18. pii: 2039. [Epub ahead of print]22(4):

Myocardial Hypertrophy and Compensatory Increase in Systolic Function in a Mouse Model of Oxidative Stress.

Rohan Varshney, Rojina Ranjit, Ying Ann Chiao, Michael Kinter, Bumsoo Ahn.

  Free radicals, or reactive oxygen species, have been implicated as one of the primary causes of myocardial pathologies elicited by chronic diseases and age. The imbalance between pro-oxidants and antioxidants, termed "oxidative stress", involves several pathological changes in mouse hearts, including hypertrophy and cardiac dysfunction. However, the molecular mechanisms and adaptations of the hearts in mice lacking cytoplasmic superoxide dismutase (Sod1KO) have not been investigated. We used echocardiography to characterize cardiac function and morphology in vivo. Protein expression and enzyme activity of Sod1KO were confirmed by targeted mass spectrometry and activity gel. The heart weights of the Sod1KO mice were significantly increased compared with their wildtype peers. The increase in heart weights was accompanied by concentric hypertrophy, posterior wall thickness of the left ventricles (LV), and reduced LV volume. Activated downstream pathways in Sod1KO hearts included serine-threonine kinase and ribosomal protein synthesis. Notably, the reduction in LV volume was compensated by enhanced systolic function, measured by increased ejection fraction and fractional shortening. A regulatory sarcomeric protein, troponin I, was hyper-phosphorylated in Sod1KO, while the vinculin protein was upregulated. In summary, mice lacking cytoplasmic superoxide dismutase were associated with an increase in heart weights and concentric hypertrophy, exhibiting a pathological adaptation of the hearts to oxidative stress.

Keywords:  CuZnSOD; myocardial hypertrophy; oxidative stress; reactive oxygen species; systolic function; troponin I; vinculin

DOI:  https://doi.org/10.3390/ijms22042039
Toxicol In Vitro. 2021 Feb 27. pii: S0887-2333(21)00056-4. [Epub ahead of print] 105131

PTEN mediates serum deprivation-induced cytotoxicity in H9c2 cells via the PI3K/AKT signaling pathway.

Mengmeng Gong, Zhiqiang Li, Xingxu Zhang, Baoxin Liu, Jiachen Luo, Xiaoming Qin, Yidong Wei.

  The pathogenesis of acute myocardial infarction (AMI) is associated with cardiomyocyte necrosis and apoptosis. Numerous studies have determined the regulatory effects of Phosphatase and tensin homolog (PTEN) cell proliferation and apoptosis in other cell types. However, the potential role of PTEN in cardiomyocyte is unclear. In this study, we used H9c2 cells cultured under serum deprivation to simulate the apoptosis process of myocardial infarction. Small interference RNA (siRNA) of PTEN was used to knock down the expression of PTEN. Cell viability was determined by CCK-8. Cell proliferation was examined by Edu staining, and the protein expression was analyzed by Western blot. We also evaluated the generation of ROS, the degree of DNA damage, and cell apoptosis using immunofluorescence assay. As a result, we observed that serum deprivation in H9c2 cells increased PTEN expression. Functionally, the PTEN knockdown experiment using siRNA inhibited serum deprivation-induced cell apoptosis, ROS production, and DNA damage, whereas increased cell proliferation. All these effects could be reversed by phosphatidylinositol 3-kinase (PI3K) inhibitor, which indicated the PI3K/protein kinase B (AKT) might be the critical component of the PTEN effects during serum deficiency. In conclusion, our study indicated the role of the PTEN/PI3K/AKT pathway in serum deprivation-induced cytotoxicity in H9c2 cells.

Keywords:  Cell apoptosis; DNA damage; H9c2; PTEN/PI3K/AKT; ROS production; Serum deprivation

DOI:  https://doi.org/10.1016/j.tiv.2021.105131
J Mol Endocrinol. 2021 Feb 01. pii: JME-20-0314.R1. [Epub ahead of print]

Role of AMPK in the protective effects exerted by triiodothyronine in ischemic-reperfused myocardium.

Romina Hermann, Victoria Evangelina Mestre Cordero, María de Las Mercedes Fernández Pazos, Mailen Florencia Córdoba, Federico Joaquín Reznik, Débora Elisabet Vélez, Andrea Lorena Fellet, María Gabriela Marina Prendes.

Recent studies have provided evidence that triiodothyronine (T3) might play an effective role in the recovery of ischemic myocardium, through the preservation of mitochondrial function and the improvement of energy substrate metabolism. To this respect, it has been suggested that T3 could activate AMP-activated protein kinase (AMPK), the cellular 'fuel-gauge' enzyme, although its role has yet to be elucidated. The aim of the present study was to investigate the effects produced by acute treatment with T3 (60 nM) and the pharmacological inhibition of AMPK by compound C, on isolated rat left atria subjected to 75 min simulated ischemia-75 min reperfusion. Results showed that T3 increased AMPK activation during simulated ischemia-reperfusion, while compound C prevented it. At the end of simulated reperfusion, acute T3 treatment increased contractile function recovery and cellular viability conservation. Mitochondrial ultrastructure was better preserved in the presence of T3, as well as mitochondrial ATP production rate and tissue ATP content. Calcium retention capacity, parameter widely used as an indicator of the resistance of mitochondrial permeability transition pore (MPTP) to opening, and GSK-3 phosphorylation, a master switch enzyme that limits MPTP opening, were increased by T3 administration. All these beneficial effects exerted by T3 acute treatment were prevented when compound C was co-administrated. The present study provided original evidence that T3 enhances intrinsic activation of AMPK during myocardial ischemia-reperfusion, being this enzyme involved, at least in part, in the protective effects exerted by T3, contributing to mitochondrial structure and function preservation, post-ischemic contractile recovery and conservation cellular viability.

DOI: https://doi.org/10.1530/JME-20-0314
J Mol Cell Cardiol. 2021 Mar 02. pii: S0022-2828(21)00051-1. [Epub ahead of print]

Computational model of cardiomyocyte apoptosis identifies mechanisms of tyrosine kinase inhibitor-induced cardiotoxicity.

Monika E Grabowska, Bryan Chun, Raquel Moya, Jeffrey J Saucerman.

  Despite clinical observations of cardiotoxicity among cancer patients treated with tyrosine kinase inhibitors (TKIs), the molecular mechanisms by which these drugs affect the heart remain largely unknown. Mechanistic understanding of TKI-induced cardiotoxicity has been limited in part due to the complexity of tyrosine kinase signaling pathways and the multi-targeted nature of many of these drugs. TKI treatment has been associated with reactive oxygen species generation, mitochondrial dysfunction, and apoptosis in cardiomyocytes. To gain insight into the mechanisms mediating TKI-induced cardiotoxicity, this study constructs and validates a computational model of cardiomyocyte apoptosis, integrating intrinsic apoptotic and tyrosine kinase signaling pathways. The model predicts high levels of apoptosis in response to sorafenib, sunitinib, ponatinib, trastuzumab, and gefitinib, and lower levels of apoptosis in response to nilotinib and erlotinib, with the highest level of apoptosis induced by sorafenib. Knockdown simulations identified AP1, ASK1, JNK, MEK47, p53, and ROS as positive functional regulators of sorafenib-induced apoptosis of cardiomyocytes. Overexpression simulations identified Akt, IGF1, PDK1, and PI3K among the negative functional regulators of sorafenib-induced cardiomyocyte apoptosis. A combinatorial screen of the positive and negative regulators of sorafenib-induced apoptosis revealed ROS knockdown coupled with overexpression of FLT3, FGFR, PDGFR, VEGFR, or KIT as a particularly potent combination in reducing sorafenib-induced apoptosis Network simulations of combinatorial treatment with sorafenib and the antioxidant N-acetyl cysteine (NAC) suggest that NAC may protect cardiomyocytes from sorafenib-induced apoptosis.

Keywords:  Apoptosis; Cardiomyocyte; Cardiotoxicity; Computational model; Systems biology; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.yjmcc.2021.02.014
J Clin Invest. 2021 Mar 01. pii: 146821. [Epub ahead of print]131(5):

YAP/TFEB pathway promotes autophagic cell death and hypertrophic cardiomyopathy in lysosomal storage diseases.

Inna Rabinovich-Nikitin, Lorrie A Kirshenbaum.

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases characterized by lysosomal enzyme deficiency. The cardiac phenotype includes cardiomyopathy with eventual heart failure. Lysosome-mediated degradation processes, such as autophagy, maintain cellular homeostasis by discarding cellular debris and damaged organelles. Under stress, the transcription factor EB (TFEB) moves into the nucleus to activate transcription of lysosome biogenesis and autophagic proteins. In this issue of the JCI, Ikeda et al. report on their exploration of the signaling pathway involved with regulating lysosomal proteins specifically in the heart. The researchers generated a mouse model for LSD that was restricted to cardiac tissue. Unexpectedly, modulation of TFEB alone was insufficient to fully rescue the underlying clearance defect in lysosomal-associated disorders. The authors identified the Yes-associated protein (YAP)/TFEB signaling pathway as a key regulator of autophagosomes. These findings suggest that undigested autophagosomes accumulate and result in the cell death and cardiac dysfunction observed with LSD.

DOI: https://doi.org/10.1172/JCI146821
Nutrients. 2021 Feb 26. pii: 737. [Epub ahead of print]13(3):

Preconditioning with Short-term Dietary Restriction Attenuates Cardiac Oxidative Stress and Hypertrophy Induced by Chronic Pressure Overload.

Miyuki Kobara, Nessa Naseratun, Hiroe Toba, Tetsuo Nakata.

  Left ventricular (LV) hypertrophy and associated heart failure are becoming a more prevalent and critical public health issue with the aging of society, and are exacerbated by reactive oxygen species (ROS). Dietary restriction (DR) markedly inhibits senescent changes; however, prolonged DR is difficult. We herein investigated whether preconditioning with short-term DR attenuates chronic pressure overload-induced cardiac hypertrophy and associated oxidative stress. Male c57BL6 mice were randomly divided into an ad libitum (AL) diet or 40% restricted diet (DR preconditioning, DRPC) group for 2 weeks prior to ascending aortic constriction (AAC), and all mice were fed ad libitum after AAC surgery. Two weeks after surgery, pressure overload by AAC increased LV wall thickness in association with LV diastolic dysfunction and promoted myocyte hypertrophy and cardiac fibrosis in the AL+AAC group. Oxidative stress in cardiac tissue and mitochondria also increased in the AL+AAC group in association with increments in cardiac NADPH oxidase-derived and mitochondrial ROS production. LV hypertrophy and associated cardiac dysfunction and oxidative stress were significantly attenuated in the DRPC+AAC group. Moreover, less severe mitochondrial oxidative damage in the DRPC+AAC group was associated with the suppression of mitochondrial permeability transition and cardiac apoptosis. These results indicate that chronic pressure overload-induced cardiac hypertrophy in association with cardiac and mitochondrial oxidative damage were attenuated by preconditioning with short-term DR.

Keywords:  apoptosis; cardiac hypertrophy; dietary restriction; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/nu13030737
Am J Physiol Heart Circ Physiol. 2021 Mar 05.

Cardiac myosin binding protein-C phosphorylation accelerates β-cardiac myosin detachment rate in mouse myocardium.

Bertrand C W Tanner, Michael J Previs, Yuan Wang, Jeffrey Robbins, Bradley M Palmer.

  Cardiac myosin binding protein-C (cMyBP-C) is a thick filament protein that modulates cardiac contraction-relaxation through its phosphorylation. Phosphorylation of cMyBP-C and ablation of cMyBP-C have been shown to increase the rate of MgADP release in the acto-myosin crossbridge cycle in the intact sarcomere. The influence of cMyBP-C on Pi-dependent myosin kinetics has not yet been examined. We investigated the effect of cMyBP-C and its phosphorylation on myosin kinetics in demembranated papillary muscle strips bearing the b-cardiac myosin isoform from non-transgenic (NTGβ) and transgenic mice lacking cMyBP-C (t/tβ). We used quick stretch and stochastic length-perturbation analysis to characterize rates of myosin detachment and force development over 0-12 mM Pi. Protein kinase-A (PKA) treatment was applied to half the strips to probe the effect of cMyBP-C phosphorylation on Pi-sensitivity of myosin kinetics. Increasing Pi increased myosin crossbridge detachment rate similarly for muscles with and without cMyBP-C, although these rates were higher in muscle without cMyBP-C. Treating myocardial strips with PKA accelerated detachment rate when cMyBP-C was present over all Pi, but not when cMyBP-C was absent. The rate of force development increased with Pi in all muscles. However, Pi sensitivity of the rate force development was reduced when cMyBP-C was present vs. absent, suggesting that cMyBP-C inhibits Pi-dependent reversal of the power stroke or stabilizes crossbridge attachment to enhance the probability of completing the power stroke. PKA treatment reduces the role for cMyBP-C to slow myosin detachment and thus effectively accelerates b-myosin detachment in the intact myofilament lattice.

Keywords:  cardiac; myofilament

DOI:  https://doi.org/10.1152/ajpheart.00673.2020
Nat Commun. 2021 Mar 05. 12(1): 1483

Cytotoxic CD8+ T cells promote granzyme B-dependent adverse post-ischemic cardiac remodeling.

Icia Santos-Zas, Jeremie Lemarié, Ivana Zlatanova, Marine Cachanado, Jean-Christophe Seghezzi, Hakim Benamer, Pascal Goube, Marie Vandestienne, Raphael Cohen, Maya Ezzo, Vincent Duval, Yujiao Zhang, Jin-Bo Su, Alain Bizé, Lucien Sambin, Philippe Bonnin, Maxime Branchereau, Christophe Heymes, Corinne Tanchot, José Vilar, Clement Delacroix, Jean-Sebastien Hulot, Clement Cochain, Patrick Bruneval, Nicolas Danchin, Alain Tedgui, Ziad Mallat, Tabassome Simon, Bijan Ghaleh, Jean-Sébastien Silvestre, Hafid Ait-Oufella.

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction.

DOI: https://doi.org/10.1038/s41467-021-21737-9
Antioxidants (Basel). 2021 Feb 24. pii: 335. [Epub ahead of print]10(3):

Effects of Apocynin on Heart Muscle Oxidative Stress of Rats with Experimental Diabetes: Implications for Mitochondria.

Estefanía Bravo-Sánchez, Donovan Peña-Montes, Sarai Sánchez-Duarte, Alfredo Saavedra-Molina, Elizabeth Sánchez-Duarte, Rocío Montoya-Pérez.

  Diabetes mellitus (DM) constitutes one of the public health problems today. It is characterized by hyperglycemia through a defect in the β-cells function and/or decreased insulin sensitivity. Apocynin has been tasted acting directly as an NADPH oxidase inhibitor and reactive oxygen species (ROS) scavenger, exhibiting beneficial effects against diabetic complications. Hence, the present study's goal was to dissect the possible mechanisms by which apocynin could mediate its cardioprotective effect against DM-induced oxidative stress. Male Wistar rats were assigned into 4 groups: Control (C), control + apocynin (C+A), diabetes (D), diabetes + apocynin (D+A). DM was induced with streptozotocin. Apocynin treatment (3 mg/kg/day) was applied for 5 weeks. Treatment significantly decreased blood glucose levels and insulin resistance in diabetic rats. In cardiac tissue, ROS levels were higher, and catalase enzyme activity was reduced in the D group compared to the C group; the apocynin treatment significantly attenuated these responses. In heart mitochondria, Complexes I and II of the electron transport chain (ETC) were significantly enhanced in the D+A group. Total glutathione, the level of reduced glutathione (GSH) and the GSH/ oxidized glutathione (GSSG) ratio were increased in the D+A group. Superoxide dismutase (SOD) and the glutathione peroxidase (GSH-Px) activities were without change. Apocynin enhances glucose uptake and insulin sensitivity, preserving the antioxidant defense and mitochondrial function.

Keywords:  antioxidant; apocynin; diabetes; heart mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/antiox10030335