Inhibition of miR-23a attenuates doxorubicin-induced mitochondria-dependent cardiomyocyte apoptosis by targeting the PGC-1α/Drp1 pathway

Background and purpose: Doxorubicin (Dox)-induced cardiotoxicity limits its clinical use. A number of microRNAs (miRs) have been found essential in Dox-induced cardiotoxicity. The aim of the present study was to elucidate the effects of miR-23a on Dox-induced cardiomyocyte apoptosis and underlying mechanisms. Experimental approach: Dox-induced cardiotoxicity model was established in primary neonatal rat ventricular myocytes (NRVMs). MTT assay, Live/Dead staining was employed to examine the viability and cell death of NRVMs. Mitochondria] membrane potential (MMP) and reactive oxygen species (ROS) were measured. Protein levels of mitochondria biogenesis and fission/fusion associated factors including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), dynamin-related protein-1 (Drp1) and mitofusin 2 (Mfn2) were detected. Meanwhile, apoptosis-related cytochrome c (Cyt c) and caspase-3 expression were examined by western blot. PGC-1 alpha siRNA was employed to validate the role of miR-23a in Dox-induced cardiotoxicity. Key results: MiR-23a expression was significantly increased by Dox concentration-dependently. Inhibition of miR-23a markedly increased viability and MMP, reduced cell death and ROS production of NRVMs. MiR-23a mimic significantly inhibited expression of its target PGC-1 alpha. MiR-23a inhibitor significantly diminished phosphorylation of Drp1 without affecting Mfn2 expression. Protein expression of Cyt c and cleaved caspase-3 were markedly inhibited by miR-23a inhibitor. The protective effects of miR-23a inhibitor were reversed by PGC-1 alpha siRNA. Conclusions and implications: Increased miR-23a promoted mitochondrial injury in the Dox-induced cellular model. Inhibition of miR-23a attenuated cardiomyocyte damage by directly targeting PGC-la/p-Drp1, thereby inhibiting mitochondria-dependent apoptosis. These findings may provide a new potential target for the treatment of Dox-induced cardiotoxicity.