Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3

Lori A. Kubasiak, Olga M. Hernandez, Nanette Bishopric, Keith A Webster

Research output: Contribution to journalArticle

345 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)12825-12830
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number20
DOIs
StatePublished - Oct 1 2002

Fingerprint

Acidosis
Cardiac Myocytes
Ischemia
Proteins
Cell Death
Apoptosis
Cell Hypoxia
Antisense Oligonucleotides
Glycolysis
DNA Fragmentation
Caspases
Muscle Cells
Myocardial Ischemia
Blood Vessels
Hypoxia
Coronary Artery Disease
Lactic Acid
Mitochondria
Necrosis
Heart Failure

Keywords

  • Antisense
  • Apoptosis
  • Heart
  • Ischemia
  • Mitochondria

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. / Kubasiak, Lori A.; Hernandez, Olga M.; Bishopric, Nanette; Webster, Keith A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 20, 01.10.2002, p. 12825-12830.

Research output: Contribution to journalArticle

Kubasiak, Lori A. ; Hernandez, Olga M. ; Bishopric, Nanette ; Webster, Keith A. / Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 20. pp. 12825-12830.
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