Sirt6 protects cardiomyocytes against doxorubicin-induced cardiotoxicity by inhibiting P53/Fas-dependent cell death and augmenting endogenous antioxidant defense mechanisms
التفاصيل البيبلوغرافية
العنوان:
Sirt6 protects cardiomyocytes against doxorubicin-induced cardiotoxicity by inhibiting P53/Fas-dependent cell death and augmenting endogenous antioxidant defense mechanisms
Sirt6, a class III NAD+-dependent deacetylase of the sirtuin family, is a highly specific 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 doxorubicin-induced 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.
