PMID- 15299040
OWN - NLM
STAT- MEDLINE
DCOM- 20041221
LR  - 20161124
IS  - 0022-0949 (Print)
IS  - 0022-0949 (Linking)
VI  - 207
IP  - Pt 18
DP  - 2004 Aug
TI  - A unique pathway of cardiac myocyte death caused by hypoxia-acidosis.
PG  - 3189-200
AB  - 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 
      approximately 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.
FAU - Graham, Regina M
AU  - Graham RM
AD  - Department of Molecular and Cellular Pharmacology and the Vascular Biology 
      Institute, University of Miami Medical Center, Miami, FL 33101, USA.
FAU - Frazier, Donna P
AU  - Frazier DP
FAU - Thompson, John W
AU  - Thompson JW
FAU - Haliko, Shannon
AU  - Haliko S
FAU - Li, Huifang
AU  - Li H
FAU - Wasserlauf, Bernard J
AU  - Wasserlauf BJ
FAU - Spiga, Maria-Grazia
AU  - Spiga MG
FAU - Bishopric, Nanette H
AU  - Bishopric NH
FAU - Webster, Keith A
AU  - Webster KA
LA  - eng
GR  - HL HL07109/HL/NHLBI NIH HHS/United States
GR  - HL07294/HL/NHLBI NIH HHS/United States
GR  - HL44578/HL/NHLBI NIH HHS/United States
GR  - HL69812/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - J Exp Biol
JT  - The Journal of experimental biology
JID - 0243705
RN  - 0 (BNIP3 protein, human)
RN  - 0 (DNA, Complementary)
RN  - 0 (Membrane Proteins)
RN  - 0 (Proto-Oncogene Proteins)
SB  - IM
MH  - Acidosis/*metabolism/physiopathology
MH  - Apoptosis/*physiology
MH  - Blotting, Northern
MH  - Blotting, Western
MH  - Cell Fractionation
MH  - Cells, Cultured
MH  - DNA, Complementary/metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Hypoxia/*metabolism/physiopathology
MH  - Membrane Proteins/metabolism
MH  - Mitochondria/metabolism
MH  - Myocardial Ischemia/*physiopathology
MH  - Myocytes, Cardiac/*metabolism/physiology
MH  - Oligonucleotide Array Sequence Analysis
MH  - Proto-Oncogene Proteins/metabolism
RF  - 75
EDAT- 2004/08/10 05:00
MHDA- 2004/12/22 09:00
CRDT- 2004/08/10 05:00
PHST- 2004/08/10 05:00 [pubmed]
PHST- 2004/12/22 09:00 [medline]
PHST- 2004/08/10 05:00 [entrez]
AID - 207/18/3189 [pii]
AID - 10.1242/jeb.01109 [doi]
PST - ppublish
SO  - J Exp Biol. 2004 Aug;207(Pt 18):3189-200. doi: 10.1242/jeb.01109.