Intact mitochondrial electron transport function is essential for signalling by hydrogen peroxide in cardiac myocytes.

Abstract

Oxidative stress has been proposed as a mediator of cardiac injury during ischemia and reperfusion. We examined the signalling events initiated by short-term exposure of cardiac myocytes to oxidative stress elicited by hydrogen peroxide. A potent stimulation of tyrosine phosphorylation was observed within 1 to 2 min exposure to 1 m m hydrogen peroxide. Within 5 min, the ERK mitogen-activated protein kinases (ERK MAPKs) were activated. This activation of ERK MAPKs was blocked by N-acetylcysteine (NAC), implicating a role for free radicals in the signalling events. NAC failed to inhibit ERK MAPK activation by the hypertrophic agent, phenylephrine, or hyperosmotic shock. Myxothiazol, an inhibitor of complex III of the mitochondrial electron transport chain, also inhibited ERK MAPK activation by hydrogen peroxide, but not by 12- O -tetradecanoylphorbol-13-acetate (TPA) or hyperosmotic shock. Myxothiazol completely inhibited the increase in tyrosine phosphorylated proteins observed with hydrogen peroxide treatment. A variety of inhibitors which act at different levels of the mitochondrial electron transport chain (rotenone, theonyltrifluoroacetone, antimycin A, cyanide) also inhibited activation of the ERK MAPKs by hydrogen peroxide but not TPA or hyperosmotic shock. These studies suggest a novel mechanism of regulation of the ERK MAPK pathway and oxidative stress signalling by hydrogen peroxide.

• Authors: M A Bogoyevitch, D C Ng, N W Court, K A Draper, A Dhillon, L Abas
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 32 Issue 8 Pg. 1469-80 (Aug 2000) ISSN: 0022-2828 [Print] England
• PMID: 10900173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2000 Academic Press.

Chemical References

• Antifungal Agents
• Enzyme Inhibitors
• Free Radicals
• Methacrylates
• Thiazoles
• Uncoupling Agents
• Phenylephrine
• Tyrosine
• myxothiazol
• Hydrogen Peroxide
• Glutathione Transferase
• Protein Kinases
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Animals, Newborn
• Antifungal Agents (pharmacology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Electron Transport
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Fluorescent Antibody Technique
• Free Radicals
• Glutathione Transferase (metabolism)
• Heart Ventricles (metabolism)
• Hydrogen Peroxide (pharmacology)
• Immunoblotting
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Methacrylates
• Mitochondria (metabolism, physiology)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Myocardium (metabolism)
• Osmotic Pressure
• Oxidative Stress
• Phenylephrine (pharmacology)
• Phosphorylation
• Protein Kinases (metabolism)
• Rats
• Signal Transduction
• Thiazoles (pharmacology)
• Time Factors
• Tyrosine (metabolism)
• Uncoupling Agents (pharmacology)