Viral myocarditis (VMC) is a common myocardial inflammatory disease characterized by inflammatory cell infiltration and cardiomyocyte necrosis. Sema3A was reported to reduce cardiac inflammation and improve cardiac function after myocardial infarction, but its role in VMC remains to be explored. Here, a VMC mouse model was established by infection with CVB3, and Sema3A was overexpressed in vivo by intraventricular injection of an adenovirus‐mediated Sema3A expression vector (Ad‐Sema3A). We found that Sema3A overexpression attenuated CVB3‐induced cardiac dysfunction and tissue inflammation. And Sema3A also reduced macrophage accumulation and NLRP3 inflammasome activation in the myocardium of VMC mice. In vitro, LPS was used to stimulate primary splenic macrophages to mimic the macrophage activation state in vivo. Activated macrophages were co‐cultured with primary mouse cardiomyocytes to evaluate macrophage infiltration‐induced cardiomyocyte damage. Ectopic expression of Sema3A in cardiomyocytes effectively protected cardiomyocytes from activated macrophage‐induced inflammation, apoptosis, and ROS accumulation. Mechanistically, cardiomyocyte‐expressed Sema3A mitigated macrophage infiltration‐caused cardiomyocyte dysfunction by promoting cardiomyocyte mitophagy and hindering NLRP3 inflammasome activation. Furthermore, NAM (a SIRT1 inhibitor) reversed the protective effect of Sema3A against activated macrophage‐induced cardiomyocyte dysfunction by suppressing cardiomyocyte mitophagy. In conclusion, Sema3A promoted cardiomyocyte mitophagy and suppressed inflammasome activation by regulating SIRT1, thereby attenuating macrophage infiltration‐induced cardiomyocyte injury in VMC.
The cardioprotective effects of different aerobic exercises on chronic heart failure with different aetiologies and whether mitophagy is involved remain elusive. In the current research, left anterior descending ligation and transverse aortic constriction surgeries were used to establish mouse models of heart failure, followed by 8 weeks of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT). The results showed that for ischaemic heart failure MICT significantly improved ejection fraction (P < 0.05) and fractional shortening (P < 0.05), mitigated left ventricular end-systolic dimension (P < 0.01), decreased brain natriuretic peptide (P < 0.0001) and mitigated fibrosis (P < 0.0001), while HIIT only decreased brain natriuretic peptide (P < 0.0001) and fibrosis (P < 0.0001). For pressure-overload heart failure, both MICT and HIIT significantly increased ejection fraction (P < 0.0001) and fractional shortening (MICT: P < 0.001, HIIT: P < 0.0001), and reduced left ventricular end-diastolic and end-systolic dimensions, brain natriuretic peptide (P < 0.0001), and fibrosis (MICT: P < 0.01, HIIT: P < 0.0001); HIIT was even better in reducing brain natriuretic peptide. Myocardial autophagy and mitophagy were compromised in heart failure, and the exercises improved myocardial autophagic flux and mitophagy inconsistently in heart failure with different aetiologies. Significant correlations were found between multiple mitophagy pathways and the cardioprotection of the exercises. Collectively, MICT may be the 'optimum' modality for ischaemic heart failure, while both MICT and HIIT (especially HIIT) were suitable for pressure-overload heart failure. Exercises differently improved myocardial autophagy/mitophagy, and multiple mitophagy-related pathways were closely implicated in cardioprotection of exercises for chronic heart failure.
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