Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis

Background-The importance of free radical homeostasis and apoptosis in norm al and diseased hearts and their interrelationships are poorly defined. We tested whether reactive oxygen species can trigger apoptosis in cardiomyocy tes, and we explored the underlying pathways. Methods and Results-A cell culture model of isolated cardiac cells and diff erent reactive oxygen species (ROS)generating systems were used. Apoptosis became evident when cardiomyocytes were exposed to either H2O2 or superoxid e anion (O-2(-)) Both H2O2- and O-2(-)-induced apoptosis of cardiomyocytes were associated with an increase in p53 protein content, whereas protein le vels of Bar and Bcl-2 were unaltered. H2O2, but not O-2(-), induced an incr ease in the protein content of Bad. Furthermore, H2O2, elicited translocati on of Bar and Rad from cytosol to mitochondria, where these factors formed heterodimers with Bcl-2, which was followed by the release of cytochrome c, activation of CPP32, and cleavage of poly(ADP-ribose) polymerase. Interest ingly, this pathway was not activated by O-2(-). Instead, O-2(-) used Mch2 alpha to promote the apoptotic pathway, as revealed by the activation of Mc h2 alpha and the cleavage of its substrate, lamin A. Conclusions-Taken together, these results indicate that ROS may play an imp ortant pathophysiological role in cardiac diseases characterized by apoptot ic cell death and suggest that different ROS-induced activations of the apo ptotic cell death program in cardiomyocytes involve distinct signaling path ways.