Apoptosis in heart failure

Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy

J. Narula, P. Pandey, E. Arbustini, N. Haider, N. Narula, F. D. Kolodgie, B. Dal Bello, M. J. Semigran, A. Bielsa-Masdeu, G. W. Dec, S. Israels, M. Ballester, R. Virmani, S. Saxena, S. Kharbanda

Research output: Contribution to journalArticle

475 Citations (Scopus)

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 δ 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.

Original languageEnglish
Pages (from-to)8144-8149
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number14
DOIs
Publication statusPublished - Jul 6 1999

Fingerprint

Cytochromes c
Cardiomyopathies
Caspase 3
Mitochondria
Heart Failure
Apoptosis
Cardiac Myocytes
Cysteine Proteases
Poly(ADP-ribose) Polymerases
Myofibrils
Motor Vehicles
Heart Transplantation
Left Ventricular Function
Immunoblotting
Cytosol
Muscle Cells
Protein Kinase C
Accidents
Electron Microscopy
Peptide Hydrolases

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Apoptosis in heart failure : Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. / Narula, J.; Pandey, P.; Arbustini, E.; Haider, N.; Narula, N.; Kolodgie, F. D.; Dal Bello, B.; Semigran, M. J.; Bielsa-Masdeu, A.; Dec, G. W.; Israels, S.; Ballester, M.; Virmani, R.; Saxena, S.; Kharbanda, S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 14, 06.07.1999, p. 8144-8149.

Research output: Contribution to journalArticle

Narula, J, Pandey, P, Arbustini, E, Haider, N, Narula, N, Kolodgie, FD, Dal Bello, B, Semigran, MJ, Bielsa-Masdeu, A, Dec, GW, Israels, S, Ballester, M, Virmani, R, Saxena, S & Kharbanda, S 1999, 'Apoptosis in heart failure: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy', Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 14, pp. 8144-8149. https://doi.org/10.1073/pnas.96.14.8144
Narula, J. ; Pandey, P. ; Arbustini, E. ; Haider, N. ; Narula, N. ; Kolodgie, F. D. ; Dal Bello, B. ; Semigran, M. J. ; Bielsa-Masdeu, A. ; Dec, G. W. ; Israels, S. ; Ballester, M. ; Virmani, R. ; Saxena, S. ; Kharbanda, S. / Apoptosis in heart failure : Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 14. pp. 8144-8149.
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