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

Abstract

Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts 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 motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage 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 associated with activation of caspase-3 and cleavage of its substrate protein kinase C ␦ but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.

Lipoptosis

“…It was shown in mice and rats that lipotoxic cardiomyopathy is caused by accumulation of cardio-toxic lipids, which can induce the death of cardiac monocytes (4,5). Similar data on heart failure induced by lipid accumulation were obtained for humans by analyzing postmortem samples (6,7). The interference with the lipid content in tumor cells by antibodies might be a novel strategy of cancer therapy.…”

Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3

“…Moreover, Hsp27 functions as an inhibitor of cas-3 activation by associating with and limiting the availability of cas-3 for cleavage by active cas-9. The release of cyt c from mitochondria is induced by exposure to STSP, diverse DNA damaging agents and ischemia (Kharbanda et al, 1997a;Kluck et al, 1997;Li et al, 1997;Liu et al, 1996;Yang et al, 1997;Zou et al, 1997;Narula et al, 1999). Other studies have shown that cyt c release is inhibited by the anti-apoptotic Bcl-2 and Bcl-x L proteins (Kharbanda et al, 1997a;Yang et al, 1997).…”

The coexistence of nocturnal sustained hypoxia and obesity additively increases cardiac apoptosis

“…The occurrence of apoptosis has been reported to contribute to the loss of cardiomyocytes in cardiomyopathies and is recognized as a predictor of adverse outcomes in subjects with cardiac diseases or heart failure (27). The "extrinsic" Fas receptor-dependent (type I) apoptotic pathway is believed to be one of the major pathways directly triggering cardiac apoptosis (7,16).…”