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

M Akao1, A Ohler, B O'Rourke

  • 1Institute of Molecular Cardiobiology, The Johns Hopkins University, Baltimore, Md, USA.

Circulation Research
|June 23, 2001
PubMed

Insights

Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels protect heart cells from apoptosis. Opening these channels with drugs like diazoxide prevents cell death markers, suggesting a new therapeutic target.

Area of Science:

  • Cell Biology
  • Mitochondrial Function
  • Apoptosis Research

Background:

  • Mitochondria play a dual role in cell death, either promoting or preventing it.
  • Cytochrome c release and mitochondrial membrane potential (DeltaPsi) loss are key to apoptosis.
  • Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels are implicated in ischemic preconditioning and protection against injury.

Purpose of the Study:

  • To investigate the relationship between mitoK(ATP) channels and apoptosis in cardiac myocytes.
  • To determine if activating mitoK(ATP) channels can prevent apoptosis induced by oxidative stress.

Main Methods:

  • Cultured neonatal rat cardiac ventricular myocytes were treated with hydrogen peroxide to induce apoptosis.
  • Apoptosis markers including TUNEL positivity, cytochrome c translocation, and caspase-3 activation were assessed.
  • MitoK(ATP) channel openers (diazoxide, pinacidil) and an antagonist (5-hydroxydecanoate) were used to probe channel function.
  • Mitochondrial membrane potential (DeltaPsi) was measured using flow cytometry and image analysis.

Main Results:

  • Hydrogen peroxide induced significant markers of apoptosis, including DeltaPsi dissipation.
  • Pharmacological opening of mitoK(ATP) channels with diazoxide preserved mitochondrial integrity and suppressed apoptosis.
  • Diazoxide prevented DeltaPsi depolarization in a concentration-dependent manner.
  • These protective effects were mimicked by pinacidil and blocked by 5-hydroxydecanoate.

Conclusions:

  • A novel mitochondrial pathway protective against apoptosis has been identified.
  • MitoK(ATP) channels are key mediators of this protective pathway.
  • MitoK(ATP) channels represent a promising therapeutic target for diseases involving apoptosis and oxidative stress.

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