Myocardial Expression of Baculoviral p35 Alleviates Doxorubicin-Induced Cardiomyopathy in Rats

The clinical use of doxorubicin, one of the most effective antitumor drugs, is limited by its cardiotoxicity, which results in irreversible cardiomyopathy and congestive heart failure. This study aimed to evaluate a gene therapy approach using adenovirus-mediated expression of p35, a baculoviral antiapoptotic gene, for alleviating doxorubicin-induced cardiomyopathy. In cultured neonatal rat cardiomyocytes, transduction with a recombinant adenoviral vector expressing p35 (Ad2/CMVp35) but not a control adenoviral vector expressing no transgene (Ad2/CMVEV) significantly inhibited doxorubicin-induced increase in cellular reactive oxygen species (ROS), the activity of caspases 8 and 3, cytochrome c release, and apoptosis. Direct injection of Ad2/CMVp35 into the left ventricular wall inhibited myocardial caspase 3 activity and apoptosis and improved left ventricular performance in rats treated with doxorubicin, whereas the same dose of Ad2/CMV β gal encoding β-galactosidase had no effect. These results suggest ...