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CELLULAR AND MITOCHONDRIAL METABOLISM

HL-1 mouse cardiomyocyte injury and death after simulated ischemia and reperfusion: roles of pH, Ca²⁺-independent phospholipase A₂, and Na⁺/H⁺ exchange

Department of Biology, University of Copenhagen, Copenhagen, Denmark

Submitted 16 July 2008 ; accepted in final form 25 February 2009

The Ca²⁺-independent phospholipase A₂ VI (iPLA₂-VI) and the Na⁺/H⁺ exchanger isoform 1 (NHE1) are highly pH-sensitive proteins that exert both protective and detrimental effects in cardiac ischemia-reperfusion. Here, we investigated the role of extracellular pH (pH_o) in ischemia-reperfusion injury and death and in regulation and function of iPLA₂-VI and NHE1 under these conditions. HL-1 cardiomyocytes were exposed to simulated ischemia (SI; 0.5% O₂, 8 mM K⁺, and 20 mM lactate) at pH_o 6.0 and 7.4, with or without 4 or 8 h of reperfusion (SI/R). Cytochrome c release and caspase-3 activation were reduced after acidic compared with neutral SI, whereas necrotic death, estimated as glucose-6-phosphate dehydrogenase release, was similar in the two conditions. Inhibition of iPLA₂-VI activity by bromoenol lactone (BEL) elicited cardiomyocyte necrosis during normoxia and after acidic, yet not after neutral, SI. The isoform-selective enantiomers R- and S-BEL both mimicked the effect of racemic BEL after acidic SI. In contrast, inhibition of NHE activity by EIPA had no significant effect on necrosis after SI. Both neutral and acidic SI were associated with a reversible loss of F-actin and cortactin integrity. Inhibition of iPLA₂-VI disrupted F-actin, cortactin, and mitochondrial integrity, whereas inhibition of NHE slightly reduced stress fiber content. iPLA₂-VIA and NHE1 mRNA levels were reduced during SI and upregulated in a pH_o-dependent manner during SI/R. This also affected the subcellular localization of iPLA₂-VIA. Thus, the mode of cell death and the roles and regulation of iPLA₂-VI and NHE1 are at least in part determined by the pH_o during SI. In addition to having clinically relevant implications, these findings can in part explain the contradictory results obtained from previous studies of iPLA₂-VIA and NHE1 during cardiac I/R.

cytoskeleton; cell death; extracellular pH; NHE1; iPLA₂; EIPA; necrosis

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