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First published online August 6, 2004
Journal of Experimental Biology 207, 3189-3200 (2004)
Published by The Company of Biologists 2004
doi: 10.1242/jeb.01109
Review Article |
A unique pathway of cardiac myocyte death caused by hypoxia–acidosis
Department of Molecular and Cellular Pharmacology and the Vascular Biology Institute, University of Miami Medical Center, Miami, FL 33101, USA
* Author for correspondence (e-mail: kwebster{at}chroma.med.miami.edu)
Accepted 20 May 2004
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.
Key words: cardiac myocyte, heart, apoptosis, ischemia, pH, BNIP3, mitochondria, necrosis
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