bims-cesiha Biomed News
on Cell signalling in the heart
Issue of 2021‒02‒07
27 papers selected by
Danae Angelidaki
Max Planck Institute for Biology of Ageing

  1. Front Pharmacol. 2020 ;11 572637
    Liu X, Han W, An N, Cao N, Wu T, Yang S, Ding L, Chen X, Chen C, Aruhan , Zhang Y, Wang K, Suo L, Huang J, Wang J, Zhao X, Zhu J, Zhang Y, Yang B.
      Cardiac fibrosis is a common pathological manifestation accompanied by various heart diseases, and antifibrotic therapy is an effective strategy to prevent diverse pathological processes of the cardiovascular system. We currently report the pharmacological evaluation of a novel anthraquinone compound (1,8-dihydroxy-6-methyl-9,10-anthraquinone-3-oxy ethyl succinate) named Kanglexin (KLX), as a potent cardioprotective agent with antifibrosis activity. Our results demonstrated that the administration of KLX by intragastric gavage alleviated cardiac dysfunction, hypertrophy, and fibrosis induced by transverse aortic constriction (TAC) surgical operation. Meanwhile, KLX administration relieved endothelial to mesenchymal transition of TAC mice. In TGF β1-treated primary cultured adult mouse cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs), KLX inhibited cell proliferation and collagen secretion. Also, KLX suppressed the transformation of fibroblasts to myofibroblasts in CFs. Further studies revealed that KLX-mediated cardiac protection was due to the inhibitory role of TGF-β1/ERK1/2 noncanonical pathway. In summary, our study indicates that KLX attenuated cardiac fibrosis and dysfunction of TAC mice, providing a potentially effective therapeutic strategy for heart pathological remodeling.
    Keywords:  Extracellular Regulated Kinase 1/2 (ERK1/2); Kanglexin; Transforming Growth Factor β1 (TGF β1); anthraquinone; cardiac fibrosis
  2. Acta Pharmacol Sin. 2021 Feb 05.
    Wang JD, Shao Y, Liu D, Liu NY, Zhu DY.
      Rictor is a key component of the mammalian target of rapamycin complex 2 (mTORC2) and is required for Akt phosphorylation (Ser473). Our previous study shows that knockdown of Rictor prevents cardiomyocyte differentiation from mouse embryonic stem (ES) cells and induces abnormal electrophysiology of ES cell-derived cardiomyocytes (ESC-CMs). Besides, knockdown of Rictor causes down-expression of connexin 43 (Cx43), the predominant gap junction protein, that is located in both the sarcolemma and mitochondria in cardiomyocytes. Mitochondrial Cx43 (mtCx43) plays a crucial role in mitochondrial function. In this study, we used the model of cardiomyocyte differentiation from mouse ES cells to elucidate the mechanisms for the mitochondrial damage in ESC-CMs after knockdown of Rictor. We showed swollen and ruptured mitochondria were observed after knockdown of Rictor under transmission electron microscope. ATP production and mitochondrial transmembrane potential were significantly decreased in Rictor-knockdown cells. Furthermore, knockdown of Rictor inhibited the activities of mitochondrial respiratory chain complex. The above-mentioned changes were linked to inhibiting the translocation of Cx43 into mitochondria by knockdown of Rictor. We revealed that knockdown of Rictor inactivated the mTOR/Akt signalling pathway and subsequently decreased HDAC6 expression, resulted in Hsp90 hyper-acetylation caused by HDAC6 inhibition, thus, inhibited the formation of Hsp90-Cx43-TOM20 complex. In conclusion, the mitochondrial Cx43 participates in shRNA-Rictor-induced mitochondrial function damage in the ESC-CMs.
    Keywords:  Connexin43; Rictor/mTORC2; cardiomyocyte differentiation; embryonic stem cell; mitochondria
  3. Endocrinology. 2021 Mar 01. pii: bqab001. [Epub ahead of print]162(3):
    Cui N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Tanaka M, Wei Y, Kakihara S, Zhao Y, Aruga K, Kawagishi H, Nakada T, Yamada M, Shindo T.
      Adrenomedullin (AM) is a peptide hormone with multiple physiological functions, which are regulated by its receptor activity-modifying proteins, RAMP2 and RAMP3. We previously reported that AM or RAMP2 knockout (KO) (AM-/-, RAMP2-/-) is embryonically lethal in mice, whereas RAMP3-/- mice are apparently normal. AM, RAMP2, and RAMP3 are all highly expressed in the heart; however, their functions there are not fully understood. Here, we analyzed the pathophysiological functions of the AM-RAMP2 and AM-RAMP3 systems in hearts subjected to cardiovascular stress. Cardiomyocyte-specific RAMP2-/- (C-RAMP2-/-) and RAMP3-/- showed no apparent heart failure at base line. After 1 week of transverse aortic constriction (TAC), however, C-RAMP2-/- exhibited significant cardiac hypertrophy, decreased ejection fraction, and increased fibrosis compared with wild-type mice. Both dP/dtmax and dP/dtmin were significantly reduced in C-RAMP2-/-, indicating reduced ventricular contractility and relaxation. Exposing C-RAMP2-/- cardiomyocytes to isoproterenol enhanced their hypertrophy and oxidative stress compared with wild-type cells. C-RAMP2-/- cardiomyocytes also contained fewer viable mitochondria and showed reduced mitochondrial membrane potential and respiratory capacity. RAMP3-/- also showed reduced systolic function and enhanced fibrosis after TAC, but those only became apparent after 4 weeks. A reduction in cardiac lymphatic vessels was the characteristic feature in RAMP3-/-. These observations indicate the AM-RAMP2 system is necessary for early adaptation to cardiovascular stress through regulation of cardiac mitochondria. AM-RAMP3 is necessary for later adaptation through regulation of lymphatic vessels. The AM-RAMP2 and AM-RAMP3 systems thus play separate critical roles in the maintenance of cardiovascular homeostasis against cardiovascular stress.
    Keywords:  adrenomedullin; cardiac fibrosis; cardiac hypertrophy; heart failure; lymphatic vessel; mitochondria
  4. Elife. 2021 Feb 02. pii: e62174. [Epub ahead of print]10
    Ito J, Omiya S, Rusu MC, Ueda H, Murakawa T, Tanada Y, Abe H, Nakahara K, Asahi M, Taneike M, Nishida K, Shah AM, Otsu K.
      Heart failure is a major public health problem, and abnormal iron metabolism is common in patients with heart failure. Although iron is necessary for metabolic homeostasis, it induces a programmed necrosis. Iron release from ferritin storage is through nuclear receptor coactivator 4 (NCOA4)-mediated autophagic degradation, known as ferritinophagy. However, the role of ferritinophagy in the stressed heart remains unclear. Deletion of Ncoa4 in mouse hearts reduced left ventricular chamber size and improved cardiac function along with the attenuation of the upregulation of ferritinophagy-mediated ferritin degradation 4 weeks after pressure overload. Free ferrous iron overload and increased lipid peroxidation were suppressed in NCOA4-deficient hearts. A potent inhibitor of lipid peroxidation, ferrostatin-1, significantly mitigated the development of pressure overload-induced dilated cardiomyopathy in wild-type mice. Thus, the activation of ferritinophagy results in the development of heart failure, whereas inhibition of this process protects the heart against hemodynamic stress.
    Keywords:  autophagy; biochemistry; chemical biology; ferritin; heart failure; iron; medicine; mouse; necrosis
  5. Circ Res. 2021 Feb 03.
    Dorn LE, Lawrence WR, Petrosino J, Xu X, Hund TJ, Whitson BA, Stratton MS, Janssen PM, Mohler PJ, Schlosser A, Sørensen GL, Accornero F.
      Rationale: Cardiac hypertrophy, a major risk factor for heart failure, occurs when cardiomyocytes remodel in response to complex signaling induced by injury or cell stress. Although cardiomyocytes are the ultimate effectors of cardiac hypertrophy, non-myocyte populations play a large yet understudied role in determining how cardiomyocytes respond to stress.Objective: To identify novel paracrine regulators of cardiomyocyte hypertrophic remodeling. Methods and Results:: We have identified a novel role for a non-myocyte-derived and TGFbeta1-induced extracellular matrix protein Microfibrillar-associated protein 4 (MFAP4) in the pathophysiology of cardiac remodeling. We have determined that non-myocyte cells are the primary sources of MFAP4 in the heart in response to TGFbeta1 stimulation. Furthermore, we have demonstrated a crucial role of MFAP4 in the cardiac adaptation to stress. Global knockout of MFAP4 led to increased cardiac hypertrophy and worsened cardiac function following chronic pressure overload. Also, one week of angiotensin-mediated neurohumoral stimulation was sufficient to exacerbate cardiomyocyte hypertrophy in MFAP4 null mice. In contrast, administration of exogenous MFAP4 to isolated cardiomyocytes blunted their phenylephrine-induced hypertrophic growth through an integrin-dependent mechanism. Finally, MFAP4 deficiency leads to dysregulated integration of G protein-coupled receptor and integrin signaling in the heart.Conclusions: Altogether, our results demonstrate a critical paracrine role of MFAP4 in the development of cardiac hypertrophy and could inform future treatment options for heart failure patients.
    Keywords:  TGFbeta; cardiomyocyte hypertrophy; integrin signaling
  6. Cardiovasc Res. 2021 Feb 04. pii: cvab036. [Epub ahead of print]
    Bertero E, Dudek J, Cochain C, Delgobo M, Ramos G, Gerull B, Higuchi T, Vaeth M, Zernecke A, Frantz S, Hofmann U, Maack C.
      The interplay between the cardiovascular system, metabolism, and inflammation plays a central role in the pathophysiology of a wide spectrum of cardiovascular diseases, including heart failure. Here, we provide an overview of the fundamental aspects of the interrelation between inflammation and metabolism, ranging from the role of metabolism in immune cell function to the processes how inflammation modulates systemic and cardiac metabolism. Furthermore, we discuss how disruption of this immuno-metabolic interface is involved in the development and progression of cardiovascular disease, with a special focus on heart failure. Finally, we present new technologies and therapeutic approaches that have recently emerged and hold promise for the future of cardiovascular medicine.
  7. J Am Heart Assoc. 2021 Jan 30. e014311
    Zhao J, Jiang X, Liu J, Ye P, Jiang L, Chen M, Xia J.
      Background Heart pathological hypertrophy has been recognized as a predisposing risk factor for heart failure and arrhythmia. DUSP (dual-specificity phosphatase) 26 is a member of the DUSP family of proteins, which has a significant effect on nonalcoholic fatty liver disease, neuroblastoma, glioma, and so on. However, the involvement of DUSP26 in cardiac hypertrophy remains unclear. Methods and Results Our study showed that DUSP26 expression was significantly increased in mouse hearts in response to pressure overload as well as in angiotensin II-treated cardiomyocytes. Cardiac-specific overexpression of DUSP26 mice showed attenuated cardiac hypertrophy and fibrosis, while deficiency of DUSP26 in mouse hearts resulted in increased cardiac hypertrophy and deteriorated cardiac function. Similar effects were also observed in cellular hypertrophy induced by angiotensin II. Importantly, we showed that DUSP26 bound to transforming growth factor-β activated kinase 1 and inhibited transforming growth factor-β activated kinase 1 phosphorylation, which led to suppression of the mitogen-activated protein kinase signaling pathway. In addition, transforming growth factor-β activated kinase 1-specific inhibitor inhibited cardiomyocyte hypertrophy induced by angiotensin II and attenuated the exaggerated hypertrophic response in DUSP26 conditional knockout mice. Conclusions Taken together, DUSP26 was induced in cardiac hypertrophy and protected against pressure overload induced cardiac hypertrophy by modulating transforming growth factor-β activated kinase 1-p38/ c-Jun N-terminal kinase-signaling axis. Therefore, DUSP26 may provide a therapeutic target for treatment of cardiac hypertrophy and heart failure.
    Keywords:  DUSP26; TAK1; cardiac hypertrophy; heart failure
  8. BMC Dev Biol. 2021 Feb 03. 21(1): 6
    Ali M, Liccardo D, Cao T, Tian Y.
      BACKGROUND: Cardiomyocytes proliferate rapidly during fetal life but lose their ability of proliferation soon after birth. However, before terminal withdrawal from the cell cycle, cardiomyocytes undergo another round of cell cycle during early postnatal life in mice. While a transient wave of increased DNA synthesis in cardiomyocyte has been observed in postnatal mouse hearts, the molecular mechanisms describing cardiomyocyte cell cycle re-entry remain poorly understood. Atrial and B-type natriuretic peptides (ANP and BNP) are abundantly expressed in embryonic heart ventricles. After birth, the expression of both genes is strongly reduced in the ventricular myocardium. Forkhead O (FOXO) transcription factors are expressed in both embryonic and postnatal heart ventricles. Their transcriptional activity negatively affects cardiomyocyte proliferation. Upon phosphorylation, FOXO is translocated to the cytoplasm and is transcriptionally inactive. Despite these important findings, it remains largely unknown whether natriuretic peptides and FOXO cooperatively play a role in regulating cardiomyocyte cell cycle activity during early postnatal life.RESULTS: We observed that the expression of ANP and BNP and the level of phosphorylated FOXO were transiently increased in the postnatal mouse heart ventricles, which coincided with the burst of cardiomyocyte cell cycle re-entry during early postnatal life in mice. Cell culture studies showed that ANP/BNP signaling and FOXO cooperatively promoted cell cycle activity in neonatal mouse cardiomyocytes. The enhanced cell cycle activity observed in combined treatment of ANP/BNP and dominant-negative FOXO (DN-FOXO), which can bind FOXO recognition sites on DNA but cannot activate transcription, was primarily mediated through natriuretic peptide receptor 3 (Npr3). In mice, simultaneous application of ANP and DN-FOXO in postnatal hearts reactivated cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction.
    CONCLUSIONS: Our data demonstrate the cooperative effects of natriuretic peptide and DN-FOXO on promoting cardiomyocyte cell cycle activity and mouse cardiac repair and regeneration after injury.
    Keywords:  ANP; BNP; Cardiomyocyte; Cell cycle activity; FOXO; Natriuretic peptide signaling; Neonatal heart
  9. Front Pharmacol. 2020 ;11 600953
    Zhang W, Liu J, Fu Y, Ji H, Fang Z, Zhou W, Fan H, Zhang Y, Liao Y, Yang T, Wang X, Yuan W, Chen X, Dong YF.
      Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type Ⅲ collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-β1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-β1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.
    Keywords:  fibrosis; heart failure with preserved ejection fraction; high-salt diet; sacubitril/valsartan; vascular injury
  10. J Cell Mol Med. 2021 Feb 01.
    Chen L, Li S, Zhu J, You A, Huang X, Yi X, Xue M.
      Myocardial infarction (MI) commonly leads to cardiomyocyte apoptosis and heart failure. Mangiferin is a natural glucosylxanthone extracted from mango fruits and leaves, which has anti-apoptotic and anti-inflammatory properties in experimental cardiovascular diseases. In the present study, we investigated the role and detailed mechanism of mangiferin in MI. We used ligation of the left anterior descending coronary artery to establish an MI model in vivo, and cardiomyocyte-specific Sirt1 knockout mice were used to identify the mechanism of mangiferin. For in vitro studies, oxygen and glucose deprivation (OGD) was used to mimic ischaemia in H9c2 cardiomyocytes. In mice, mangiferin treatment increased Sirt1 expression after MI, significantly reduced the infarct area, and prevented MI-induced apoptosis and heart failure. Mangiferin reduced OGD-induced cellular apoptosis in H9c2 cells. Meanwhile, Sirt1 knockout/silencing abolished the protective effects of mangiferin. Further studies revealed that mangiferin increased FoxO3a deacetylation by up-regulating Sirt1, thus preventing apoptosis, and adenovirus-mediated constitutive acetylation of FoxO3a restricted the anti-apoptotic effects of mangiferin in vivo and in vitro. Our results indicate that mangiferin prevents cardiomyocyte apoptosis and the subsequent heart failure by activating the Sirt1/FoxO3a pathway in MI, and suggest that mangiferin may have an interesting potential in following studies towards clinical evaluation.
    Keywords:  FoxO3a; apoptosis; mangiferin; myocardial infarction; sirt1
  11. Sci Adv. 2021 Feb;pii: eabe3706. [Epub ahead of print]7(6):
    Majumdar U, Manivannan S, Basu M, Ueyama Y, Blaser MC, Cameron E, McDermott MR, Lincoln J, Cole SE, Wood S, Aikawa E, Lilly B, Garg V.
      Calcific aortic valve disease (CAVD) is an increasingly prevalent condition, and endothelial dysfunction is implicated in its etiology. We previously identified nitric oxide (NO) as a calcification inhibitor by its activation of NOTCH1, which is genetically linked to human CAVD. Here, we show NO rescues calcification by an S-nitrosylation-mediated mechanism in porcine aortic valve interstitial cells and single-cell RNA-seq demonstrated NO regulates the NOTCH pathway. An unbiased proteomic approach to identify S-nitrosylated proteins in valve cells found enrichment of the ubiquitin-proteasome pathway and implicated S-nitrosylation of USP9X (ubiquitin specific peptidase 9, X-linked) in NOTCH regulation during calcification. Furthermore, S-nitrosylated USP9X was shown to deubiquitinate and stabilize MIB1 for NOTCH1 activation. Consistent with this, genetic deletion of Usp9x in mice demonstrated CAVD and human calcified aortic valves displayed reduced S-nitrosylation of USP9X. These results demonstrate a previously unidentified mechanism by which S-nitrosylation-dependent regulation of a ubiquitin-associated pathway prevents CAVD.
  12. Biol Chem. 2021 Jan 30.
    Ding L, Li S, Wang F, Xu J, Li S, Wang B, Kou J, Wang Y, Cao W.
      Multiple studies have showed that berberine protects against heart diseases, including obesityassociated cardiomyopathy. However, it is not fully disclosed the potential molecular mechanisms of berberine on controlling cardiac remodelling. Kruppel-like factor (KLF) 4, identified as a critical transcriptional factor, participates in multiple cardiac injuries. The present study was to explore whether KLF4 determined the cardioprotective benefits of berberine in dietary-induced obese mice. High fat diet-induced obese mice were treated with berberine with or without lentivirus encoding Klf4 siRNA, and cardiac parameters were analysed by multiple biological approaches. In dietary-induced obese mouse model, administration of berberine obviously increased cardiac level of KLF4, which closely correlated with improvement of cardiac functional parameters. Co-treatment of lentivirus encoding Klf4 siRNA abolished cardioprotective benefits of berberine, including induction of cardiac hypertrophy, fibrosis, functional disorders, inflammatory response and oxidative stress. Mechanistically, we found berberine improved cardiac mitochondrial biogenesis and activities, whereas silencing Klf4 decreased berberine-upregulated mitochondrial quality, ATP production and oxygen consumption. Our present study demonstrated that berberine protected against dietary-induced cardiac structural disorders and mitochondrial dysfunction dependent on cardiac KLF4 signaling. Cardiac KLF4 was one of potential therapeutic targets for obesityinduced cardiac injuries.
    Keywords:  Kruppel-like factor 4; berberine; cardiomyopathy; mitochondria; obesity
  13. Sci Adv. 2021 Jan;pii: eabb3991. [Epub ahead of print]7(2):
    Dhandapany PS, Kang S, Kashyap DK, Rajagopal R, Sundaresan NR, Singh R, Thangaraj K, Jayaprakash S, Manjunath CN, Shenthar J, Lebeche D.
      Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart muscle disease characterized by hypertrophy with preserved or increased ejection fraction in the absence of secondary causes. However, recent studies have demonstrated that a substantial proportion of individuals with HCM also have comorbid diabetes mellitus (~10%). Whether genetic variants may contribute a combined phenotype of HCM and diabetes mellitus is not known. Here, using next-generation sequencing methods, we identified novel and ultrarare variants in adiponectin receptor 1 (ADIPOR1) as risk factors for HCM. Biochemical studies showed that ADIPOR1 variants dysregulate glucose and lipid metabolism and cause cardiac hypertrophy through the p38/mammalian target of rapamycin and/or extracellular signal-regulated kinase pathways. A transgenic mouse model expressing an ADIPOR1 variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that ADIPOR1 variants can cause HCM and provide new insights into ADIPOR1 regulation.
  14. Pharmacol Res. 2021 Jan 29. pii: S1043-6618(20)31722-9. [Epub ahead of print] 105414
    Singh R, Kaundal RK, Zhao B, Bouchareb R, Lebeche D.
      Cardiac fibrosis is characterized by excessive deposition of extracellular matrix proteins and myofibroblast differentiation. Our previous findings have implicated resistin in cardiac fibrosis; however, the molecular mechanisms underlying this process are still unclear. Here we investigated the role of resistin in fibroblast-to-myofibroblast differentiation and elucidated the pathways involved in this process. Fibroblast-to-myofibroblast transdifferentiation was induced with resistin or TGFβ1 in NIH-3T3 and adult cardiac fibroblasts. mRNA and protein expression of fibrotic markers were analyzed by qPCR and immunoblotting. Resistin-knockout mice, challenged with a high-fat diet (HFD) for 20 weeks to stimulate cardiac impairment, were analyzed for cardiac function and fibrosis using histologic and molecular methods. Cardiac fibroblasts stimulated with resistin displayed increased fibroblast-to-myofibroblast conversion, with increased levels of αSma, col1a1, Fn, Ccn2 and Mmp9, with remarkable differences in the actin network appearance. Mechanistically, resistin promotes fibroblast-to-myofibroblast transdifferentiation and fibrogenesis via JAK2/STAT3 and JNK/c-Jun signaling pathways, independent of TGFβ1. Resistin-null mice challenged with HFD showed an improvement in cardiac function and a decrease in tissue fibrosis and reduced mRNA levels of fibrogenic markers. These findings are the first to delineate the role of resistin in the process of cardiac fibroblast-to-myofibroblast differentiation via JAK/STAT3 and JNK/c-Jun pathways, potentially leading to stimulation of cardiac fibrosis.
    Keywords:  Fibroblast/Myofibroblast differentiation; JAK2/STAT3; JNK/c-Jun; Myocardial Fibrosis; Resistin; SP600125: JNK inhibitor; WP1066: JAK2 inhibitor
  15. J Cell Mol Med. 2021 Feb 06.
    Wang J, Bai J, Duan P, Wang H, Li Y, Zhu Q.
      Previous studies have shown that the expression of inwardly rectifying potassium channel 6.1 (Kir6.1) in heart mitochondria is significantly reduced in type 1 diabetes. However, whether its expression and function are changed and what role it plays in type 2 diabetic cardiomyopathy (DCM) have not been reported. This study investigated the role and mechanism of Kir6.1 in DCM. We found that the cardiac function and the Kir6.1 expression in DCM mice were decreased. We generated mice overexpressing or lacking Kir6.1 gene specifically in the heart. Kir6.1 overexpression improved cardiac dysfunction in DCM. Cardiac-specific Kir6.1 knockout aggravated cardiac dysfunction. Kir6.1 regulated the phosphorylation of AKT and Foxo1 in DCM. We further found that Kir6.1 overexpression also improved cardiomyocyte dysfunction and up-regulated the phosphorylation of AKT and FoxO1 in neonatal rat ventricular cardiomyocytes with insulin resistance. Furthermore, FoxO1 activation down-regulated the expression of Kir6.1 and decreased the mitochondrial membrane potential (ΔΨm) in cardiomyocytes. FoxO1 inactivation up-regulated the expression of Kir6.1 and increased the ΔΨm in cardiomyocytes. Chromatin immunoprecipitation assay demonstrated that the Kir6.1 promoter region contains a functional FoxO1-binding site. In conclusion, Kir6.1 improves cardiac dysfunction in DCM, probably through the AKT-FoxO1 signalling pathway.
    Keywords:  AKT; FoxO1; Kir6.1; cardiac dysfunction; diabetic cardiomyopathy
  16. Oxid Med Cell Longev. 2021 ;2021 6610543
    Zhang WB, Zheng YF, Wu YG.
      Doxorubicin- (DOX-) related cardiac injury impairs the life quality of patients with cancer. This largely limited the clinical use of DOX. It is of great significance to find a novel strategy to reduce DOX-related cardiac injury. Oroxylin A (OA) has been identified to exert beneficial effects against inflammatory diseases and cancers. Here, we investigated whether OA could attenuate DOX-induced acute cardiotoxicity in mice. A single dose of DOX was used to induce acute cardiac injury in mice. To explore the protective effects, OA was administered to mice for ten days beginning from five days before DOX injection. The data in our study indicated that OA inhibited DOX-induced heart weight loss, reduction in cardiac function, and the elevation in myocardial injury markers. DOX injection resulted in increased oxidative damage, inflammation accumulation, and myocardial apoptosis in vivo and in vitro, and these pathological alterations were alleviated by treatment of OA. OA activated the sirtuin 1 (Sirt1) signaling pathway via the cAMP/protein kinase A, and its protective effects were blocked by Sirt1 deficiency. OA treatment did not affect the tumor-killing action of DOX in tumor-bearing mice. In conclusion, OA protected against DOX-related acute cardiac injury via the regulation of Sirt1.
  17. JACC Basic Transl Sci. 2021 Jan;6(1): 55-70
    Gava FN, da Silva AA, Dai X, Harmancey R, Ashraf S, Omoto ACM, Salgado MC, Moak SP, Li X, Hall JE, do Carmo JM.
      Heart failure has a high mortality rate, and current therapies offer limited benefits. The authors demonstrate that activation of the central nervous system leptin-melanocortin pathway confers remarkable protection against progressive heart failure following severe myocardial infarction. The beneficial cardiac-protective actions of leptin require activation of brain melanocortin-4 receptors and elicit improvements in cardiac substrate oxidation, cardiomyocyte contractility, Ca2+ coupling, and mitochondrial efficiency. These findings highlight a potentially novel therapeutic approach for myocardial infarction and heart failure.
    Keywords:  AMPK, adenosine monophosphate–activated protein kinase; BP, blood pressure; CNS, central nervous system; HF, heart failure; HR, heart rate; ICV, intracerebroventricular; LV, left ventricular; MC4R; MC4R, melanocortin-4 receptor; MI, myocardial infarction; MTII, melanotan II; appetite; blood pressure; cardiac metabolism; heart failure; mTOR, mechanistic target of rapamycin
  18. Theranostics. 2021 ;11(7): 3052-3059
    Wu X, Li Y, Zhang S, Zhou X.
      Cell death is an important component of the pathophysiology of cardiovascular disease. An understanding of how cardiomyocytes die, and why regeneration of cells in the heart is limited, is a critical area of study. Ferroptosis is a form of regulated cell death that is characterized by iron overload, leading to accumulation of lethal levels of lipid hydroperoxides. The metabolism of iron, lipids, amino acids and glutathione tightly controls the initiation and execution of ferroptosis. Emerging evidence shows that ferroptosis is closely associated with the occurrence and progression of various diseases. In recent years, ferroptosis has been found to play critical roles in cardiomyopathy, myocardial infarction, ischemia/reperfusion injury, and heart failure. This article reviews the mechanisms by which ferroptosis is initiated and controlled and discusses ferroptosis as a novel therapeutic target for various cardiovascular diseases.
    Keywords:  cardiomyopathy; ferroptosis; heart failure; ischemia/reperfusion injury; myocardial infarction
  19. Circ Res. 2021 Feb 05. 128(3): 335-357
    Kyriazis ID, Hoffman M, Gaignebet L, Lucchese AM, Markopoulou E, Palioura D, Wang C, Bannister TD, Christofidou-Solomidou M, Oka SI, Sadoshima J, Koch WJ, Goldberg IJ, Yang VW, Bialkowska AB, Kararigas G, Drosatos K.
      RATIONALE: Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that type-1 diabetes is associated with increased cardiac expression of KLF5 (Krüppel-like factor-5) and PPARα (peroxisome proliferator-activated receptor) that regulate cardiac lipid metabolism.OBJECTIVE: In this study, we investigated the involvement of KLF5 in DbCM and its transcriptional regulation.
    METHODS AND RESULTS: KLF5 mRNA levels were assessed in isolated cardiomyocytes from cardiovascular patients with diabetes and were higher compared with nondiabetic individuals. Analyses in human cells and diabetic mice with cardiomyocyte-specific FOXO1 (Forkhead box protein O1) deletion showed that FOXO1 bound directly on the KLF5 promoter and increased KLF5 expression. Diabetic mice with cardiomyocyte-specific FOXO1 deletion had lower cardiac KLF5 expression and were protected from DbCM. Genetic, pharmacological gain and loss of KLF5 function approaches and AAV (adeno-associated virus)-mediated Klf5 delivery in mice showed that KLF5 induces DbCM. Accordingly, the protective effect of cardiomyocyte FOXO1 ablation in DbCM was abolished when KLF5 expression was rescued. Similarly, constitutive cardiomyocyte-specific KLF5 overexpression caused cardiac dysfunction. KLF5 caused oxidative stress via direct binding on NADPH oxidase (NOX)4 promoter and induction of NOX4 (NADPH oxidase 4) expression. This was accompanied by accumulation of cardiac ceramides. Pharmacological or genetic KLF5 inhibition alleviated superoxide formation, prevented ceramide accumulation, and improved cardiac function in diabetic mice.
    CONCLUSIONS: Diabetes-mediated activation of cardiomyocyte FOXO1 increases KLF5 expression, which stimulates NOX4 expression, ceramide accumulation, and causes DbCM.
    Keywords:  NADPH oxidases; ceramides; diabetic cardiomyopathy; forkhead box protein O1; oxidative stress; peroxisome proliferator-activated receptors
  20. Stem Cells Transl Med. 2021 Feb 02.
    Bi W, Wang J, Jiang Y, Li Q, Wang S, Liu M, Liu Q, Li F, Paul C, Wang Y, Yang HT.
      Acute myocardial infarction (MI) resulting from coronary ischemia is a major cause of disability and death worldwide. Transplantation of human embryonic stem cell (hESC)-derived cardiovascular progenitor cells (hCVPCs) promotes the healing of infarcted hearts by secreted factors. However, the hCVPC-secreted proteins contributing to cardiac repair remain largely unidentified. In this study, we investigated protective effects of neurotrophin (NT)-3 secreted from hCVPCs in hearts against myocardial ischemia/reperfusion (I/R) injury and explored the underlying mechanisms to determine the potential of using hCVPC products as a new therapeutic strategy. The implantation of hCVPCs into infarcted myocardium at the beginning of reperfusion following 1 hour of ischemia improved cardiac function and scar formation of mouse hearts. These beneficial effects were concomitant with reduced cardiomyocyte death and increased angiogenesis. Moreover, hCVPCs secreted a rich abundance of NT-3. The cardioreparative effect of hCVPCs in the I/R hearts was mimicked by human recombinant NT-3 (hNT-3) but canceled by NT-3 neutralizing antibody (NT-3-Ab). Furthermore, endogenous NT-3 was detected in mouse adult cardiomyocytes and its level was enhanced in I/R hearts. Adenovirus-mediated NT-3 knockdown exacerbated myocardial I/R injury. Mechanistically, hNT-3 and endogenous NT-3 inhibited I/R-induced cardiomyocyte apoptosis through activating the extracellular signal-regulated kinase (ERK) and reducing the Bim level, resulting in the cardioreparative effects of infarcted hearts together with their effects in the improvement of angiogenesis. These results demonstrate for the first time that NT-3 is a cardioprotective factor secreted by hCVPCs and exists in adult cardiomyocytes that reduces I/R-induced cardiomyocyte apoptosis via the ERK-Bim signaling pathway and promotes angiogenesis. As a cell product, NT-3 may represent as a noncell approach for the treatment of myocardial I/R injury.
    Keywords:  ERK-Bim signaling pathway; apoptosis; cardiac repair; human embryonic stem cell-derived cardiovascular progenitor cells; neurotrophin-3
  21. Mech Ageing Dev. 2021 Feb 01. pii: S0047-6374(21)00014-2. [Epub ahead of print] 111442
    Zhuang X, Sun X, Zhou H, Zhang S, Zhong X, Xu X, Guo Y, Xiong Z, Liu M, Lin Y, Zhang M, Liao X.
      Doxorubicin (Dox)-induced cardiotoxicity could lead to dilated cardiomyopathy and heart failure. Our previous study reported the protective effects of Klotho against hyperglycemia-induced cardiomyopathy. We investigated whether Klotho alleviated Dox-induced cardiotoxicity. Neonatal rat ventricular cardiomyocytes and H9c2 cells were incubated with 5 μM Dox for 24 h with or without Klotho (0.1 μg/ml). Dox-induced cardiotoxicity model was approached in C57BL/6 mice. Cardiac function and serum enzyme activity, apoptosis and mitochondrial dysfunction were measured. We found that pretreatment with Klotho significantly reduced Dox-induced apoptosis in cardiomyocytes. In Dox-treated mice, Klotho also suppressed cardiac cell death and improved cardiac function. Moreover, the expression of Dynamin-related protein 1 (Drp1) was increased after Dox-treatment both in vitro and in vivo, which was related to apoptosis in cardiomyocytes. In vitro experiments, Drp1 ser 616 phosphorylation post-Dox stimulation could be significantly attenuated by Klotho or Drp1 specific inhibitor Mdivi-1. Overexpression of Drp1 in cardiomyocytes increased Dox-induced heart injury which could also be attenuated by Klotho. This study demonstrated that Klotho alleviated Dox-induced cardiotoxicity by reducing apoptosis and mitochondrial fission through down-regulating Drp1 expression. Our findings highlighted new targets for the therapy of Dox-induced cardiomyopathy.
    Keywords:  Cardiotoxicity; Doxorubicin; Drp1; Klotho; Mitochondrial fission
  22. Cell Regen. 2021 Feb 01. 10(1): 3
    Li H, Chang C, Li X, Zhang R.
      As a highly conserved signaling pathway in metazoans, the Notch pathway plays important roles in embryonic development and tissue regeneration. Recently, cardiac injury and regeneration have become an increasingly popular topic for biomedical research, and Notch signaling has been shown to exert crucial functions during heart regeneration as well. In this review, we briefly summarize the molecular functions of the endocardial Notch pathway in several cardiac injury and stress models. Although there is an increase in appreciating the importance of endocardial Notch signaling in heart regeneration, the mechanism of its activation is not fully understood. This review highlights recent findings on the activation of the endocardial Notch pathway by hemodynamic blood flow change in larval zebrafish ventricle after partial ablation, a process involving primary cilia, mechanosensitive ion channel Trpv4 and mechanosensitive transcription factor Klf2.
    Keywords:  Heart regeneration; Hemodynamic alteration; Ion channel; Notch signaling; Primary cilium; klf2
  23. Front Physiol. 2020 ;11 609157
    Bai J, Liu C, Zhu P, Li Y.
      Cardiovascular complication is one of the significant causes of death in diabetic mellitus (DM) in which diabetic cardiomyopathy, independent of hypertension, cardiac valvular disease, and coronary atherosclerosis, occupies an important position. Although the detailed pathogenesis of diabetic cardiomyopathy remains unclear currently, mitochondrial morphological abnormality and dysfunction were observed in diabetic cardiomyopathy animal models according to much research, suggesting that mitochondrial structural and functional impairment played an integral role in the formation of diabetic cardiomyopathy. Thus, we have summarized the effect of mitochondria on the process of diabetic cardiomyopathy, including abnormal mitochondrial morphology, mitochondrial energy metabolism disorder, enhanced mitochondrial oxidative stress, mitochondrial unbalanced calcium homeostasis, and mitochondrial autophagy. Based on the above mechanisms and the related evidence, more therapeutic strategies targeting mitochondria in diabetic cardiomyopathy have been and will be proposed to delay the progression of the disease.
    Keywords:  calcium homeostasis; diabetic cardiomyopathy; energy metabolism; mitochondria; mitochondrial autophagy; mitochondrial morphology; oxidative stress
  24. Front Bioeng Biotechnol. 2020 ;8 615850
    Liang C, Liu Y, Xu H, Huang J, Shen Y, Chen F, Luo M.
      Background: Acute myocardial infarction (AMI) is one of the leading causes of morbidity and death worldwide. Studies have indicated that microRNAs in mesenchymal stem cell (MSC)-derived exosomes are crucial for treating various diseases.Methods: Human umbilical cord MSC (hucMSC)-derived exosomes (hucMSC-exo) were isolated and used to treat cardiomyocytes that underwent hypoxia/reoxygenation (H/R) injury. Bioluminescence assessment was used to study binding of miRNA to its targeting gene.
    Results: We found that H/R decreased the viability of AC16 cells, increased the expression of NLRP3, and activated caspase-1(p20) and GSDMD-N as well as release of IL-1β and IL-18, and such effects were abolished by administration of hucMSC-exo. Administration of exosomes from negative scramble miRNA (NC)-transfected hucMSCs blocked H/R-caused lactate dehydrogenase release, pyroptosis, and over-regulation of NLRP3 and activated caspase-1(p20) and GSDMD-N as well as release of IL-1β and IL-18. More importantly, in comparison to exsomes from NC-transfected hucMSCs, exsomes from miR-100-5p-overexpressing hucMSCs had more obvious effects, and those from miR-100-5p-inhibitor-transfected hucMSCs showed fewer effects. Functional study showed that miR-100-5p bound to the 3'-untranslated region (3'-UTR) of FOXO3 to suppress its transcription. Moreover, overexpression of FOXO3 abolished the protective effects of miR-100-5p.
    Conclusion: Enriched miR-100-5p in hucMSC-exo suppressed FOXO3 expression to inhibit NLRP3 inflammasome activation and suppress cytokine release and, therefore, protected cardiomyocytes from H/R-induced pyroptosis and injury.
    Keywords:  exosome; human umbilical cord mesenchymal stem cells; hypoxia/reoxygenation; inflammasome; miRNA
  25. J Am Heart Assoc. 2021 Feb 03. e017791
    Ruiz M, Khairallah M, Dingar D, Vaniotis G, Khairallah RJ, Lauzier B, Thibault S, Trépanier J, Shi Y, Douillette A, Hussein B, Nawaito SA, Sahadevan P, Nguyen A, Sahmi F, Gillis MA, Sirois MG, Gaestel M, Stanley WC, Fiset C, Tardif JC, Allen BG.
      Background Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2-null (MK2-/-) mice. Methods and Results Survival curves for male MK2+/+ and MK2-/- mice did not differ (Mantel-Cox test, P=0.580). At 12 weeks of age, MK2-/- mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, aging was not associated with an abnormal reduction in diastolic function. Both R-R interval and P-R segment durations were prolonged in MK2-deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca2+ transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2+/+ and MK2-/- mice. MK2-/- mice had lower body temperature and an age-dependent reduction in body weight. mRNA levels of key metabolic genes, including Ppargc1a, Acadm, Lipe, and Ucp3, were increased in hearts from MK2-/- mice. For equivalent respiration rates, mitochondria from MK2-/- hearts showed a significant decrease in Ca2+ sensitivity to mitochondrial permeability transition pore opening. Eight weeks of pressure overload increased left ventricular mass in MK2+/+ and MK2-/- mice; however, after 2 weeks the increase was significant in MK2+/+ but not MK2-/- mice. Finally, the pressure overload-induced decrease in systolic function was attenuated in MK2-/- mice 2 weeks, but not 8 weeks, after constriction of the transverse aorta. Conclusions Collectively, these results implicate MK2 in (1) autonomic regulation of heart rate, (2) cardiac mitochondrial function, and (3) the early stages of myocardial remodeling in response to chronic pressure overload.
    Keywords:  MK2; bradycardia; cardiac remodeling; mitochondrial permeability transition pore; p38 MAPK
  26. Front Physiol. 2020 ;11 623190
    Pérez-Hernández M, Marrón-Liñares GM, Schlamp F, Heguy A, van Opbergen CJM, Mezzano V, Zhang M, Liang FX, Cerrone M, Delmar M.
      Plakophilin-2 (PKP2) is classically defined as a component of the desmosome. Besides its role in cell-cell adhesion, PKP2 can modulate transcription through intracellular signals initiated at the site of cell-cell contact. Mutations in PKP2 associate with arrhythmogenic right ventricular cardiomyopathy (ARVC). Recent data demonstrate that inflammation plays a key role in disease progression; other results show an abundance of anti-heart antibodies in patients with confirmed diagnosis of ARVC. Here, we test the hypothesis that, in adult cardiac myocytes, PKP2 transcript abundance is endogenously linked to the abundance of transcripts participating in the inflammatory/immune response. Cardiac-specific, tamoxifen (TAM)-activated PKP2-knockout mice (PKP2cKO) were crossed with a RiboTag line to allow characterization of the ribosome-resident transcriptome of cardiomyocytes after PKP2 knockdown. Data were combined with informatics analysis of human cardiac transcriptome using GTEx. Separately, the presence of non-myocyte cells at the time of analysis was assessed by imaging methods. We identified a large number of transcripts upregulated consequent to PKP2 deficiency in myocytes, inversely correlated with PKP2 abundance in human transcriptomes, and part of functional pathways associated with inflammatory/immune responses. Our data support the concept that PKP2 is transcriptionally linked, in cardiac myocytes, to genes coding for host-response molecules even in the absence of exogenous triggers. Targeted anti-inflammatory therapy may be effective in ARVC.
    Keywords:  GTEx; arrhythmogenic cardiomyopathy; inflammation/immune response; plakophilin-2; transcriptome
  27. Free Radic Biol Med. 2021 Jan 27. pii: S0891-5849(21)00039-3. [Epub ahead of print]
    Huo C, Liu Y, Li X, Xu R, Jia X, Hou L, Wang X.
      Cardiac hypertrophy, an important cause of heart failure, is characterized by an increase in heart weight, the ventricular wall, and cardiomyocyte volume. The volume regulatory anion channel (VRAC) is an important regulator of cell volume. However, its role in cardiac hypertrophy remains unclear. The purpose of this study was to investigate the effect of leucine-rich repeat-containing 8A (LRRC8A), an essential component of the VRAC, on angiotensin II (AngII)-induced cardiac hypertrophy. Our results showed that LRRC8A expression, NADPH oxidase activity, and reactive oxygen species (ROS) production were increased in AngII-induced hypertrophic neonatal mouse cardiomyocytes and the myocardium of C57/BL/6 mice. In addition, AngII activated VRAC currents in cardiomyocytes. The delivery of adeno-associated viral (AAV9) bearing siRNA against mouse LRRC8A into the left ventricular wall inhibited AngII-induced cardiac hypertrophy and fibrosis. Accordingly, the knockdown of LRRC8A attenuated AngII-induced cardiomyocyte hypertrophy and VRAC currents in vitro. Furthermore, knockdown of LRRC8A suppressed AngII-induced ROS production, NADPH oxidase activity, the expression of NADPH oxidase membrane-bound subunits Nox2, Nox4, and p22phox, and the translocation of NADPH oxidase cytosolic subunits p47phox and p67phox. Immunofluorescent staining showed that LRRC8A co-localized with NADPH oxidase membrane subunits Nox2, Nox4, and p22phox. Co-immunoprecipitation and analysis of a C-terminal leucine-rich repeat domain (LRRD) mutant showed that LRRC8A physically interacts with Nox2, Nox4, and p22phox via the LRRD. Taken together, the results of this study suggested that LRRC8A might play an important role in promoting AngII-induced cardiac hypertrophy by interacting with NADPH oxidases via the LRRD.
    Keywords:  NADPH oxidase; angiotensin II; cardiac hypertrophy; leucine-rich repeat containing 8A; reactive oxygen species; volume regulatory anion channel