Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3.
Coronary artery disease leads to injury and loss of myocardial tissue by deprivation of blood flow (ischemia) and is a major underlying cause of heart failure. Prolonged ischemia causes necrosis and apoptosis of cardiac myocytes and vascular cells; however, the mechanisms of ischemia-mediated cell death are poorly understood. Ischemia is associated with both hypoxia and acidosis due to increased glycolysis and lactic acid production. We recently reported that hypoxia does not induce cardiac myocyte apoptosis in the absence of acidosis. We now report that hypoxia-acidosis-associated cell death is mediated by BNIP3, a member of the Bcl-2 family of apoptosis-regulating proteins. Chronic hypoxia induced the expression and accumulation of BNIP3 mRNA and protein in cardiac myocytes, but acidosis was required to activate the death pathway. Acidosis stabilized BNIP3 protein and increased the association with mitochondria. Cell death by hypoxia-acidosis was blocked by pretreatment with antisense BNIP3 oligonucleotides. The pathway included extensive DNA fragmentation and opening of the mitochondrial permeability transition pore, but no apparent caspase activation. Overexpression of wild-type BNIP3, but not a translocation-defective mutant, activated cardiac myocyte death only when the myocytes were acidic. This pathway may figure significantly in muscle loss during myocardial ischemia.
Kubasiak
Lori A
LA
Department of Molecular and Cellular Pharmacology, University of Miami Medical Center, Miami, FL 33136, USA.
Hernandez
Olga M
OM
Bishopric
Nanette H
NH
Webster
Keith A
KA
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D016923:Cell Death; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia; D007425:Intracellular Membranes / Q000378:metabolism; D007511:Ischemia; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009336:Necrosis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins
C090121:BNIP3 protein, human; C116838:BNIP3L protein, human; D016895:Culture Media, Serum-Free; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins