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 micromol/L) on cell death induced by oxidative stress (H2O2, 100 micromol/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.

journal_name

Circulation

journal_title

Circulation

authors

Teshima Y,Akao M,Jones SP,Marbán E

doi

10.1161/01.CIR.0000093277.20968.C7

subject

Has Abstract

pub_date

2003-11-04 00:00:00

pages

2275-81

issue

18

eissn

0009-7322

issn

1524-4539

pii

01.CIR.0000093277.20968.C7

journal_volume

108

pub_type

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