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

Nature Reviews Cardiology volume 6, pages 250–261 (2009)Cite this article

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 from eight 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.

Key Points

  • Apoptosis plays an important part in heart failure, and release of cytochrome c1 release from mitochondria to cytoplasm is a prominent feature

  • Although the apoptotic cascade is initiated in heart failure, it might not complete (so-called apoptosis interruptus)

  • Interruption of apoptotic process is most likely due to concurrent upregulation of antiapoptotic and proapoptotic factors, while AIFM1 and DFF concentrations are substantially reduced

  • Interrupted apoptosis suggests that heart failure could often represent a reversible disease state and comprise an attractive therapeutic target

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Figure 1: CASP8 in cardiomyopathic and control human hearts.
Figure 2: Death receptors in cardiomyopathic and control human hearts.
Figure 3: Cytochrome c1 distribution and nuclear morphology in control and cardiomyopathic hearts.
Figure 4: CASP9 expression in cardiomyopathic and control human hearts.
Figure 5: CASP3 in cardiomyopathic and control human hearts.
Figure 6: Regulators of CASP3 activation in cardiomyopathic and control human hearts.
Figure 7: DNA fragmentation factors in cardiomyopathy and control human hearts.
Figure 8: A schematic diagram depicting how concurrent activation of proapoptotic and antiapoptotic factors in cardiomyocytes might contribute to putative interrupted apoptotic pathways in heart failure.

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References

  1. Narula J et al. (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335: 1182–1189

    Article  CAS  Google Scholar 

  2. Olivetti G et al. (1997) Apoptosis in the failing human heart. N Engl J Med 336: 1131–1141

    Article  CAS  Google Scholar 

  3. Narula J et al. (1999) Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci USA 96: 8144–8149

    Article  CAS  Google Scholar 

  4. Narula J et al. (2006) Mechanisms of Disease: apoptosis in heart failure—seeing hope in death. Nat Clin Pract Cardiovasc Med 3: 681–688

    Article  CAS  Google Scholar 

  5. Kanoh M et al. (1999) Significance of myocytes with positive DNA in situ nick end-labeling (TUNEL) in hearts with dilated cardiomyopathy: not apoptosis but DNA repair. Circulation 99: 2757–2764

    Article  CAS  Google Scholar 

  6. Narula N et al. (2005) Is the myofibrillarlytic myocyte a forme fruste apoptotic myocyte? Ann Thorac Surg 79: 1333–1337

    Article  Google Scholar 

  7. Reed JC and Paternostro G (1999) Postmitochondrial regulation of apoptosis during heart failure. Proc Natl Acad Sci U S A 96: 7614–7616

    Article  CAS  Google Scholar 

  8. Kietselaer BL et al. (2007) Noninvasive detection of programmed cell loss with 99mTc-labeled annexin A5 in heart failure. J Nucl Med 48: 562–567

    Article  CAS  Google Scholar 

  9. Quantity One® version 4.1.1. (Bio-rad, Hercules, CA)

  10. Scheubel RJ et al. (2002) Apoptotic pathway activation from mitochondria and death receptors without caspase-3 cleavage in failing human myocardium: fragile balance of myocyte survival? J Am Coll Cardiol 39: 481–488

    Article  CAS  Google Scholar 

  11. Haider NKS et al. (1999) Caspase 3 mediated cleavage of troponin c at evolutionary conserved calcium binding site: Relevance of apoptosis in heart failure. Circulation 100 (Suppl 1): I-283

    Google Scholar 

  12. Gu J et al. (1999) Functional interaction of DFF35 and DFF45 with caspase-activated DNA fragmentation nuclease DFF40. J Biol Chem 274: 20759–20762

    Article  CAS  Google Scholar 

  13. Datta R et al. (2000) XIAP regulates DNA damage-induced apoptosis downstream of caspase-9 cleavage. J Biol Chem 275: 31733–31738

    Article  CAS  Google Scholar 

  14. Deveraux QL et al. (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17: 2215–2223

    Article  CAS  Google Scholar 

  15. Salvesen GS and Duckett CS (2002) IAP proteins: blocking the road to death's door. Nat Rev Mol Cell Biol 3: 401–410

    Article  CAS  Google Scholar 

  16. Han Z et al. (1997) A sequential two-step mechanism for the production of the mature p17:p12 form of caspase-3 in vitro. J Biol Chem 272: 13432–13436

    Article  CAS  Google Scholar 

  17. von Coelln R et al. (2001) Rescue from death but not from functional impairment: caspase inhibition protects dopaminergic cells against 6-hydroxydopamine-induced apoptosis but not against the loss of their terminals. J Neurochem 77: 263–273

    Article  CAS  Google Scholar 

  18. Communal C et al. (2002) Functional consequences of caspase activation in cardiac myocytes. Proc Natl Acad Sci USA 99: 6252–6256

    Article  CAS  Google Scholar 

  19. Birks EJ et al. (2006) Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 355: 1873–1884

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. University of California Irvine School of Medicine, Irvine, CA, USA

    Nezam Haider, Sudhir Gupta, Han Liu, Navneet Narula & Jagat Narula

  2. Center for Genetic Cardiovascular Diseases, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy

    Eloisa Arbustini

  3. Massachusetts General Hospital, Boston, MA, USA

    Roger Hajjar, Marc J Semigran & G William Dec

  4. John Radcliffe Hospital, Oxford, UK

    Narain Moorjani & Stephen Westaby

  5. University of Minnesota, Minneapolis, MN, USA

    Y Chandrashekhar

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  1. Nezam Haider
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Correspondence to Jagat Narula.

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Haider, N., Arbustini, E., Gupta, S. et al. Concurrent upregulation of endogenous proapoptotic and antiapoptotic factors in failing human hearts. Nat Rev Cardiol 6, 250–261 (2009). https://doi.org/10.1038/ncpcardio1452

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