Preconditioning rabbit cardiomyocytes: role of pH, vacuolar proton ATPase, and apoptosis

Ischemic preconditioning signals through protein kinase C (PKC) to protect against myocardial infarction. This protection is characterized by diminished intracellular acidification. Acidification is also a feature of apoptosis, and several agents act to prevent apoptosis by preventing acidification...

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Bibliographic Details
Published in:The Journal of clinical investigation 1996-05, Vol.97 (10), p.2391-2398
Main Authors: Gottlieb, R A, Gruol, D L, Zhu, J Y, Engler, R L
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Female
Hydrogen-Ion Concentration
Male
Myocardial Ischemia - metabolism
Myocardium - metabolism
Protein Kinase C - physiology
Proton-Translocating ATPases - physiology
Rabbits
Sodium-Hydrogen Exchangers - physiology
Vacuoles - enzymology
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Summary:Ischemic preconditioning signals through protein kinase C (PKC) to protect against myocardial infarction. This protection is characterized by diminished intracellular acidification. Acidification is also a feature of apoptosis, and several agents act to prevent apoptosis by preventing acidification through activation of ion channels and pumps to promote cytoplasmic alkalinization. We characterized metabolic inhibition, recovery, and preconditioning through a PKC-dependent pathway in cardiomyocytes isolated from adult rabbit hearts. Preconditioning reduced loss of viability assessed by morphology and reduced DNA nicking. Blockade of the vacuolar proton ATPase (VPATPase) prevented the effect of preconditioning to reduce metabolic inhibition-induced acidosis, loss of viability, and DNA nicking. The beneficial effect of Na+/H+ exchange inhibition, which is thought to be effective through reduced intracellular Na+ and Ca++, was also abrogated by VPATPase blockade, suggesting that acidification even in the absence of Na+/H+ exchange may lead to cell death. We conclude that a target of PKC in mediating preconditioning is activation of the VPATPase with resultant attenuation of intracellular acidification during metabolic inhibition. Inhibition of the "death protease," interleukin-1-beta converting enzyme or related enzymes, also protected against the injury that followed metabolic inhibition. This observation, coupled with the detection of DNA nicking in cells subjected to metabolic inhibition, suggests that apoptotic cell death may be preventable in this model of ischemia/reperfusion injury.
ISSN:0021-9738
DOI:10.1172/jci118683