Background: Doxorubicin (DOX) is an effective anti-tumor agent; however, it causes cardiotoxicity. SIRT1 is an NAD+-dependent protein deacetylase that plays a crucial role in cell survival.
Hypothesis: SIRT1 protects against doxorubicin-induced cardiotoxicity.
Methods and Results: In wild type (WT) and tamoxifen-inducible cardiomyocyte-specific SIRT1 knockout (SIRT1 cKO) mice, either DOX or PBS was administered (4 injections of 5 mg/kg/wk) starting at 3 months of age. Echocardiography at 1 week after final DOX showed that left ventricular dimension, thickness, and fractional shortening (FS; 32.7 vs. 33.8%) were comparable in WT-PBS and cKO-PBS groups. DOX decreased FS in both genotypes; but FS was lower in cKO-DOX than in WT-DOX (24.6% vs. 27.3%, P<0.05). Cardiac level of nitrotyrosine, a marker of oxidative stress, was higher in cKO-DOX by 68% than WT-DOX. At 12 weeks after DOX, cardiac level of ANP mRNA, a marker of heart failure, was significantly higher in cKO-DOX than WT-DOX. Protein levels of LC3-II, a marker of autophagosomes, and p62 that is degraded by autophagy were significantly higher in SIRT1 cKO, suggesting suppression of autophagy.
Conclusion: The findings suggest that SIRT1 affords protection against DOX-induced cardiotoxicity, probably via attenuating oxidative stress through activating autophagy.