Apoptosis in heart failure: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy

Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiom yopathy, progressive decline in left ventricular function,, and congestive heart failure, Because the molecular mechanisms involved in apoptosis of ca rdiocytes are not, completely understood, we studied the biochemical and ul trastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hear ts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3, The hearts explanted from five victims of mo tor vehicle accidents;or myocardial ventricular tissues from three donor he arts were used as controls, Evidence of apoptosis was observed only in ends tage cardiomyopathy, There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associate d with activation of caspase-3 and cleavage of its substrate protein kinase C delta but not poly(ADP-ribose) polymerase. By contrast there was no appa rent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls, The present study provides irt vivo evidence of cy tochrome c-dependent activation of cysteine proteases in human cardiomyopat hy. Activation of proteases supports the phenomenon of apoptosis in myopath ic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive hear t failure, the present demonstration of an activated apoptotic cascade in c ardiomyopathy could-provide the basis for novel interventional strategies.