Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells

Masaharu Akao, Andreas Ohler, Brian O'Rourke, Eduardo Marbán

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondria can either enhance or suppress cell death. Cytochrome c release from mitochondria and depolarization of the mitochondrial membrane potential (ΔΨ) are crucial events in triggering apoptosis. In contrast, activation of mitochondrial ATP-sensitive potassium (mitoKATP) channels prevents lethal ischemic injury in vivo, implicating these channels as key players in the process of ischemic preconditioning. We probed the relationship between mitoKATP channels and apoptosis in cultured neonatal rat cardiac ventricular myocytes. Incubation with 200 μmol/L hydrogen peroxide induced TUNEL positivity, cytochrome c translocation, caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and dissipation of ΔΨ. Pharmacological opening of mitoKATP channels by diazoxide (100 μmol/L) preserved mitochondrial integrity and suppressed all markers of apoptosis. Diazoxide prevented ΔΨ depolarization in a concentration-dependent manner (EC50 ≈40 μmol/L, with saturation by 100 μmol/L), as shown by both flow cytometry and quantitative image analysis of cells stained with fluorescent ΔΨindicators. These cytoprotective effects of diazoxide were reproduced by pinacidil, another mitoKATP agonist, and blocked by the mitoKATP channel antagonist 5-hydroxydecanoate (500 μmol/L). Our findings identify a novel mitochondrial pathway that is protective against apoptosis. The results also pinpoint mitoKATP channels as logical therapeutic targets in diseases of enhanced apoptosis and oxidative stress.

Original languageEnglish (US)
Pages (from-to)1267-1275
Number of pages9
JournalCirculation research
Volume88
Issue number12
DOIs
StatePublished - Jun 22 2001

Keywords

  • Apoptosis
  • Ischemia
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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