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Roles of NHE1 and iPLA2 in ischemia/reperfusion‐induced damage in HL‐1 mouse cardiomyocytes

The Na+/H+ exchanger, NHE1, and the Ca2+‐independent phospholipase A2 (iPLA2) play complex roles in modulation of cell death. Here, we address the roles of NHE1 and iPLA2, specifically iPLA2β in simulated ischemia/reperfusion (I/R) (0.5% O2, 5 h, reperfusion 4‐8 h) in HL‐1 cardiomyocytes. I/R elicited mitochondrial fragmentation, F‐actin degradation, and cell death by necrosis and other non‐caspase pathways. Cell viability after I/R was greater at pHo 6.0 than at pHo 7.4. The NHE1 inhibitor EIPA decreased cell viability and increased necrosis during normoxia and in I/R pHo 6.0. The iPLA2 inhibitor bromoenol‐lactone (BEL) substantially decreased viability and increased necrosis during normoxia and, to a lesser extent, in I/R. BEL treatment alone elicited F‐actin degradation in normoxia. NHE1 expression was reduced by 40 and 50% at the mRNA and protein level, respectively, by hypoxia, followed by an increase in mRNA level above control value during reperfusion at pHo 6.0. A comparable, yet less pronounced pattern was observed for iPLA2β. Finally, I/R elicited translocation of iPLA2β to the nuclear region. In conclusion, NHE1 and iPLA2 exert net pro‐survival effects under normoxia and in simulated I/R in HL‐1 cardiomyocytes, in part by counteracting necrotic cell death. This effect of iPLA2 is reduced by I/R, either due to iPLA2 downregulation or because of an additional, I/R‐ associated detrimental effect of iPLA2 activity.