Insulin-like growth factor I retards apoptotic signaling induced by ethanol in cardiomyocytes.

Apoptosis of cardiac muscle cells may contribute to the development of cardiomyopathy and heart failure. Alcohol (ethanol) abuse is a major cause of cardiomyopathy, but its underlying mechanism remains unknown. To determine whether ethanol causes apoptosis in cardiac muscle and whether insulin-like growth factor I (IGF 1) improves cardiac muscle survival upon ethanol exposure, we have defined the effects of ethanol and IGF I in primary cardiomyocytes. Ethanol decreased cell viability in dose-response manner from 0.2% to 1%. In contrast, ethanol (0.2-1%) did not alter viability of cardiac fibroblasts. To assess the occurrence of apoptosis, DNA fragmentation was determined with quantitation of nucleosomes. Nucleosomes were increased in ethanol-treated cells, thus confirming the apoptotic effects of ethanol. The pro-apoptotic Bax protein and Caspase 3 are important proteins of apoptotic signaling. The content of Bax and the activities of Caspase 3 were increased upon ethanol exposure. IGF I partially suppressed Bax induction, Caspase 3 activation, DNA fragmentation, and increased cardiomyocyte survival. The effects of IGF I on ethanol-induced apoptosis can be inhibited with a chemical inhibitor of PI 3 Kinase (LY-294002), suggesting that anti-apoptotic actions of IGF I involves PI 3 Kinase. These results may have important implications on further understanding the pathogenesis of alcoholic heart disease and the development of new strategies to treat alcoholic cardiomyopathy.