A unique pathway of cardiac myocyte death caused by hypoxia-acidosis

Regina M Graham, Donna P. Frazier, John W. Thompson, Shannon Haliko, Huifang Li, Bernard J. Wasserlauf, Maria Grazia Spiga, Nanette Bishopric, Keith A Webster

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Chronic hypoxia in the presence of high glucose leads to progressive acidosis of cardiac myocytes in culture. The condition parallels myocardial ischemia in vivo, where ischemic tissue becomes rapidly hypoxic and acidotic. Cardiac myocytes are resistant to chronic hypoxia at neutral pH but undergo extensive death when the extracellular pH (pH[o]) drops below 6.5. A microarray analysis of 20 000 genes (cDNAs and expressed sequence tags) screened with cDNAs from aerobic and hypoxic cardiac myocytes identified >100 genes that were induced by >2-fold and ∼20 genes that were induced by >5-fold. One of the most strongly induced transcripts was identified as the gene encoding the pro-apoptotic Bcl-2 family member BNIP3. Northern and western blot analyses confirmed that BNIP3 was induced by 12-fold (mRNA) and 6-fold (protein) during 24 h of hypoxia. BNIP3 protein, but not the mRNA, accumulated 3.5-fold more rapidly under hypoxia-acidosis. Cell fractionation experiments indicated that BNIP3 was loosely bound to mitochondria under conditions of neutral hypoxia but was translocated into the membrane when the myocytes were acidotic. Translocation of BNIP3 coincided with opening of the mitochondrial permeability pore (MPTP). Paradoxically, mitochondrial pore opening did not promote caspase activation, and broad-range caspase inhibitors do not block this cell death pathway. The pathway was blocked by antisense BNIP3 oligonucleotides and MPTP inhibitors. Therefore, cardiac myocyte death during hypoxia-acidosis involves two distinct steps: (1) hypoxia activates transcription of the death-promoting BNIP3 gene through a hypoxia-inducible factor-1 (HIF-1) site in the promoter and (2) acidosis activates BNIP3 by promoting membrane translocation. This is an atypical programmed death pathway involving a combination of the features of apoptosis and necrosis. In this article, we will review the evidence for this unique pathway of cell death and discuss its relevance to ischemic heart disease. The article also contains new evidence that chronic hypoxia at neutral pH does not promote apoptosis or activate caspases in neonatal cardiac myocytes.

Original languageEnglish
Pages (from-to)3189-3200
Number of pages12
JournalJournal of Experimental Biology
Volume207
Issue number18
DOIs
StatePublished - Aug 1 2004

Fingerprint

acidosis
hypoxia
Acidosis
Cardiac Myocytes
death
caspases
fold
gene
Genes
myocardial ischemia
Caspases
genes
apoptosis
Myocardial Ischemia
cell death
Permeability
translocation
permeability
Cell Death
Complementary DNA

Keywords

  • Apoptosis
  • BNIP3
  • Cardiac myocyte
  • Heart
  • Ischemia
  • Mitochondria
  • Necrosis
  • pH

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Agricultural and Biological Sciences (miscellaneous)

Cite this

Graham, R. M., Frazier, D. P., Thompson, J. W., Haliko, S., Li, H., Wasserlauf, B. J., ... Webster, K. A. (2004). A unique pathway of cardiac myocyte death caused by hypoxia-acidosis. Journal of Experimental Biology, 207(18), 3189-3200. https://doi.org/10.1242/jeb.01109

A unique pathway of cardiac myocyte death caused by hypoxia-acidosis. / Graham, Regina M; Frazier, Donna P.; Thompson, John W.; Haliko, Shannon; Li, Huifang; Wasserlauf, Bernard J.; Spiga, Maria Grazia; Bishopric, Nanette; Webster, Keith A.

In: Journal of Experimental Biology, Vol. 207, No. 18, 01.08.2004, p. 3189-3200.

Research output: Contribution to journalArticle

Graham, RM, Frazier, DP, Thompson, JW, Haliko, S, Li, H, Wasserlauf, BJ, Spiga, MG, Bishopric, N & Webster, KA 2004, 'A unique pathway of cardiac myocyte death caused by hypoxia-acidosis', Journal of Experimental Biology, vol. 207, no. 18, pp. 3189-3200. https://doi.org/10.1242/jeb.01109
Graham RM, Frazier DP, Thompson JW, Haliko S, Li H, Wasserlauf BJ et al. A unique pathway of cardiac myocyte death caused by hypoxia-acidosis. Journal of Experimental Biology. 2004 Aug 1;207(18):3189-3200. https://doi.org/10.1242/jeb.01109
Graham, Regina M ; Frazier, Donna P. ; Thompson, John W. ; Haliko, Shannon ; Li, Huifang ; Wasserlauf, Bernard J. ; Spiga, Maria Grazia ; Bishopric, Nanette ; Webster, Keith A. / A unique pathway of cardiac myocyte death caused by hypoxia-acidosis. In: Journal of Experimental Biology. 2004 ; Vol. 207, No. 18. pp. 3189-3200.
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