Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3
| Autor: | Keith A. Webster, Nanette H. Bishopric, Lori A. Kubasiak, Olga M. Hernandez |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Programmed cell death Necrosis Time Factors Blotting Western Ischemia Apoptosis Biology Transfection Culture Media Serum-Free Internal medicine Proto-Oncogene Proteins medicine Myocyte Animals RNA Messenger Hypoxia Muscle Skeletal Cells Cultured Acidosis Multidisciplinary Cell Death Tumor Suppressor Proteins Cardiac myocyte Cell Membrane Membrane Proteins Intracellular Membranes Biological Sciences Hydrogen-Ion Concentration Oligonucleotides Antisense medicine.disease Blotting Northern Molecular biology Mitochondria Rats Endocrinology Mitochondrial permeability transition pore Proto-Oncogene Proteins c-bcl-2 medicine.symptom Plasmids Subcellular Fractions |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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