SIRT3 and Doxorubicin-induced cardiotoxicity

Sirtuins3 (SIRT3) is NAD+-dependent deacetylase enzyme localized in the mitochondrial matrix.The critical functions of SIRT3 including regulation of metabolism, oxidative phosphorylation, decrease of oxidative stress, inhibition of apoptosis and promoting of genome fidelity. Based on these effects, loss of SIRT3 activity has been linked to cardiac dysfunction. Doxorubicin (Dox) is an anthracycline drug with a wide spectrum use in solid and hematological malignancy, nonetheless its cardiotoxic side effect has been limited the clinical significance of this anticancer agent. Doxorubicin-induced cardiotoxicity is predominantly linked to the oxidative stress. SIRT3 can attenuate oxidative stress associated doxorubicin cardiotoxicity in H9C2 via the enhancement of mitochondrial respiration efficiency and protection against mitochondrial DNA (mtDNA) damage lead to progression of cardiomyopathy. The inhibitory effect of SIRT3 on Bcl-2-like-interacting protein 3 (Bnip3) prevents DOX-induced mitochondrial injury and heart failure. SIRT3 regulates mitochondrial dynamics and protects cardiomyocytes from DOX-induced cardiotoxicity via deacetylation and activation of optic atrophy factor 1 (OPA1). Administration of DOX at the peak time of SIRT3 activity reduced DOX-induced cardiotoxicity in rats and hiPSC-CMs. Overall, increased expression and activation of SIRT3 are among the significant cellular mechanisms to protect the heart against DOX-induced cardiotoxicity