Concurrent upregulation of endogenous proapoptotic and antiapoptotic factors in failing human hearts

Nezam Haider, Eloisa Arbustini, Sudhir Gupta, Han Liu, Navneet Narula, Roger Hajjar, Narain Moorjani, Stephen Westaby, Marc J. Semigran, G. William Dec, Y. Chandrashekhar, Jagat Narula

Research output: Contribution to journalArticle

Abstract

Background: Despite widespread activation of proapoptotic stimuli and mediators, the degree of apoptosis in failing hearts is not very high. Endogenous antiapoptotic mechanisms are thought to be triggered by the heart-failure process. We investigated whether activation of endogenous apoptosis inhibitors plays a part when death receptor and mitochondrial apoptotic pathways have been triggered. Methods: We evaluated various proapoptotic and antiapoptotic factors in myocardial tissue specimens obtained from normal and explanted end-stage ischemic and dilated cardiomyopathic hearts. Caspases (CASPs) 3, 8 and 9, total and activated Bcl-2 homology domain 3-interacting domain death agonist, the X-linked inhibitor of apoptosis (XIAP), and DNA fragmentation factor (DFF) proteins were analyzed by western blotting. Expression of messenger RNA was measured by reverse-transcription polymerase chain reaction for the XIAP, DIABLO, CFLAR and DFF genes. We also assessed CASP3, CASP8 and CASP9 and DFF activity. Cytochrome c1 localization in myocytes was analyzed by immunohistochemistry and immunoelectron microscopy. Results: We collected myocardial tissue fromeight cardiomyopathic hearts and five normal hearts. Cytochrome c1 was released from mitochondria into the cytosol in the cardiomyopathic hearts but CASP9 was not activated. CASP8 activity was increased compared with that in normal myocardium. Although CASP3 was cleaved, activity was not greatly increased because of an increase in XIAP and decrease in DIABLO expression. DFF proteins were conspicuously absent. Conclusions: Concurrent upregulation of endogenous antiapoptotic mechanisms can interrupt the apoptotic cascade and prevents cell loss despite the presence of multiple proapoptotic factors. This period might offer a therapeutic window for restoration of myocardial function in heart failure.

Original languageEnglish
Pages (from-to)250-261
Number of pages12
JournalNature Clinical Practice Cardiovascular Medicine
Volume6
Issue number3
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Haider, N., Arbustini, E., Gupta, S., Liu, H., Narula, N., Hajjar, R., Moorjani, N., Westaby, S., Semigran, M. J., Dec, G. W., Chandrashekhar, Y., & Narula, J. (2009). Concurrent upregulation of endogenous proapoptotic and antiapoptotic factors in failing human hearts. Nature Clinical Practice Cardiovascular Medicine, 6(3), 250-261. https://doi.org/10.1038/ncpcardio1452