Cariporide (HOE642), a Selective Na + -H + Exchange Inhibitor, Inhibits the Mitochondrial Death Pathway

Abstract

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 μmol/L) on cell death induced by oxidative stress (H ₂ O ₂ , 100 μmol/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 H ₂ O ₂ . 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 Ca ²⁺ induced by oxidative stress. Cariporide remarkably suppressed cytosolic Na ⁺ and Ca ²⁺ accumulation. Next, we investigated the effects of cariporide on mitochondria-associated death process. Mitochondrial Ca ²⁺ overload induced by H ₂ O ₂ 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 H ₂ O ₂ . Conclusions— Cariporide protects cardiomyocytes against oxidant-induced cell death by preserving intracellular ion homeostasis and mitochondrial integrity.