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(Circulation. 2003;108:2275.)
© 2003 American Heart Association, Inc.

Basic Science Reports

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

From the Institute of Molecular Cardiobiology, Johns Hopkins University, Baltimore, Md.

Correspondence to Eduardo Marbán, MD, PhD, FACC, Institute of Molecular Cardiobiology, Johns Hopkins University, 720 Rutland Ave, 844 Ross Building, Baltimore, MD 21205. E-mail marban{at}jhmi.edu

Received May 6, 2003; revision received July 15, 2003; accepted July 16, 2003.

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 (H₂O₂, 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 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.

Key Words: ion channels • apoptosis • prevention • calcium • sodium

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