Sirt3 attenuates doxorubicin-induced cardiac hypertrophy and mitochondrial dysfunction via suppression of Bnip3

Doxorubicin (Dox) is an anthracycline antibiotic widely used in cancer treatment. Although its antitumor efficacy appears to be dose dependent, its clinical use is greatly restricted by development of cardiotoxicity. Sirtuin-3 (Sirt3) is the major deacetylase within the mitochondrial matrix that plays an important role in regulation of cardiac function. This study was performed to identify the regulatory role of Sirt3 on Dox-induced cardiac hypertrophy and mitochondrial dysfunction in rats in vivo and in vitro. We found that adenovirus-mediated overexpression of Sirt3 resulted in marked inhibition of Dox-induced cardiac hypertrophy, particularly mitochondrial dysfunction including opening of the mitochondrial permeability transition pore (mPTP), loss of mitochondrial membrane potential (Delta psi m), respiration dysfunction, and mitochondrial reactive oxygen species (ROS) production. Further study revealed that Bcl-2-like 19 kDa-interacting protein 3 (Bnip3) mRNA and protein expression levels were altered in cardiomyocytes in vivo and in vitro after Dox treatment, and these increases were significantly inhibited by Sirt3 overexpression. Interestingly, the Dox-disrupted mitochondrial Cox1-Ucp3 complexes were preserved by Sirt3 overexpression. Finally, recombinant adeno-associated virus-mediated overexpression of Bnip3 (AAV-Bnip3) in rat hearts and cardiomyocytes completely impaired the protective effects of Sirt3 on Dox-induced cardiac toxicity and mitochondrial dysfunction. These findings reveal a new molecular mechanism in which Sirt3 restores mitochondrial respiratory chain defects, and cell viability of Dox-damaged cardiomyocytes is mutually dependent on and obligatorily linked to suppression of Bnip3 gene expression. Interventions that antagonize Bnip3 may contribute to the beneficial effect of Sirt3 regarding prevention of mitochondrial injury and heart failure in cancer patients undergoing chemotherapy.