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Cardiac hypertrophy is the main cause of heart failure and sudden death in patients. But the pathogenesis is unclear. Angiotensin II may contribute to cardiac hypertrophy in response to pressure overload. In angiotensin II‐treated cardiomyocytes, there is a larger cross‐sectional area, more apoptosis cells, and a reduction of irisin expression. An increase in P62, an autophagy flux index, as well as LC3II, were observed in cardiomyocytes after angiotensin II‐induced injury. Surprisely, irisin supplementation increased LC3II expression and decreased P62 expression, consisted of results of RFP‐GFP‐LC3B adenovirus transfection, and reduced cardiomyocyte apoptosis, meanwhile, the protection of irisin was reversed by the autophagy inhibitor 3‐methyladenine. In animal experiments, overexpression of irisin reduced cardiomyocyte apoptosis and alleviated myocardial hypertrophy caused by pressure overload. The above results indicate that irisin‐induced protective autophagy and alleviated the apoptosis signaling pathway in cardiomyocytes, consequently reducing cardiomyocyte apoptosis after angiotensin II‐induced injury. Hence, increasing irisin expression may be a new way to improve cardiac function and quality of life in patients with cardiac hypertrophy.

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Sirt6, a class III NAD + -dependent deacetylase of the sirtuin family, is a highly speci c H3 deacetylase and plays important roles in regulating cellular growth and death. The induction of oxidative stress and death are the crucial mechanisms involved in cardiomyocyte damage and cardiac dysfunction in doxorubicininduced cardiotoxocity, but the regulatory role of Sirt6 in the fate of DOX-impaired cardiomyocytes is poorly understood. In this study, we exposed heterozygous Sirt6 knockout (Sirt6 +/− ) mice and their littermates as well as cultured neonatal rat cardiomyocytes to DOX, then investigated how Sirt6 mitigates oxidative stress and myocardial injury in the DOX-treated myocardium. Sirt6 partial knockout or silencing worsened myocardial damage, cardiac remodeling, and oxidative stress in mice or cultured cardiomyocytes with DOX challenge. Cardiomyocytes infected with adenoviral constructs encoding Sirt6 showed reversal of this DOX-induced damage. Intriguingly, Sirt6 reduced oxidative stress injury by upregulating endogenous antioxidant levels, interacted with oxidative stress-stirred p53, and acted as a co-repressor of p53 in nuclei. Sirt6 was recruited by p53 to the promoter regions of the target genes Fas and FasL and further suppressed p53 transcription activity by reducing histone acetylation. Sirt6 inhibited Fas/FasL signaling and attenuated both Fas-FADD-caspase-8 apoptotic and Fas-RIP3 necrotic pathways. These results suggest that Sirt6 protects the heart against DOX-induced cardiotoxity by upregulating endogenous antioxidants, as well as suppressing oxidative stress and cell death signaling pathways dependent on ROS-stirred p53 transcriptional activation, thus reducing Fas-FasL-mediated apoptosis and necrosis.