Journal
CIRCULATION
Volume 108, Issue 18, Pages 2275-2281Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.0000093277.20968.C7
Keywords
ion channels; apoptosis; prevention; calcium; sodium
Funding
- NHLBI NIH HHS [R37 HL36957] Funding Source: Medline
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Background-The Na+-H+ exchanger figures prominently in cardiac ischemia-reperfusion injury. Several experimental and clinical studies have demonstrated a cardioprotective effect of Na+-H+ exchanger inhibition; however, the precise mechanisms have not been established. Methods and Results-We examined the effects of cariporide (HOE642, 10 mumol/L) on cell death induced by oxidative stress (H2O2, 100 mumol/L) in cultured neonatal rat cardiomyocytes. Cariporide significantly suppressed markers of cell death, such as TUNEL positivity and caspase-3 cleavage, at 8 or 16 hours after H2O2. The early phase of cell death, reported by increases in phosphatidylserine exposure and propidium iodide uptake, was also inhibited by cariporide. To explore the mechanisms of cell protection, we examined the effects of cariporide on increases in intracellular Na+ and Ca2+ induced by oxidative stress. Cariporide remarkably suppressed cytosolic Na+ and Ca2+ accumulation. Next, we investigated the effects of cariporide on mitochondria-associated death process. Mitochondrial Ca2+ overload induced by H2O2 was remarkably suppressed by cariporide. Loss of mitochondrial membrane potential is a critical step of the death pathway; cariporide prevented mitochondrial membrane potential loss induced by H2O2. Conclusions-Cariporide protects cardiomyocytes against oxidant-induced cell death by preserving intracellular ion homeostasis and mitochondrial integrity.
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