Differential actions of cardioprotective agents on the mitochondrial death pathway

Masaharu Akao, Brian O'Rourke, Hideo Kusuoka, Yasushi Teshima, Steven P. Jones, Eduardo Marbán

Research output: Contribution to journalArticle

Abstract

We examined the effect of cardioprotective agents on three distinct phases of the H2O2-induced response that leads to loss of mitochondrial membrane potential (ΔΨm) and cell death in cultured cardiac myocytes: (1) priming, consisting of calcium-dependent morphological changes in mitochondria (swelling and loss of cristae), with preserved ΔΨm, (2) depolarization, the rapid ΔΨm depolarization caused by mitochondrial permeability transition pore (PTP) opening, and (3) cell fragmentation. The mitochondrial ATP-sensitive potassium (mitoKATP) channel opener diazoxide markedly decreased the likelihood that cells would undergo priming: many mitochondria remained fully polarized and morphologically intact. Diazoxide not only decreased the number of cells undergoing ΔΨm depolarization but also delayed the onset of ΔΨm loss, whereas it did not change the duration of depolarization in unprotected cells. The adenine nucleotide translocase inhibitor bongkrekic acid mimicked the effect of diazoxide to suppress priming, except that its effects were not blocked by the mitoKATP channel blocker 5-hydroxydecanoate. In contrast, the PTP inhibitor cyclosporin A (CsA) did not prevent priming: neither latency for ΔΨm depolarization nor mitochondrial morphological changes were affected. However, CsA slowed the process of depolarization and blunted its severity. Importantly, coapplication of diazoxide and CsA exhibited additive effects, improving the efficacy of protection. Activation of mitoKATP channels suppresses the cell death process at its earliest stage, by preserving mitochondrial integrity during oxidative stress. By virtue of its pharmacology and its phenotypic consequences, this mode of action is distinguishable from that of other cardioprotective interventions.

Original languageEnglish (US)
Pages (from-to)195-202
Number of pages8
JournalCirculation research
Volume92
Issue number2
DOIs
StatePublished - Feb 7 2003

Keywords

  • Cell death
  • Membrane potential
  • Mitochondria
  • Oxidative stress
  • Potassium channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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