Simvastatin attenuates oxidant-induced mitochondrial dysfunction in cardiac myocytes.
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can exert beneficial effects independently of serum cholesterol reduction by increasing the bioavailability of nitric oxide. However, it is unclear whether statins can exert such effects directly on cardiac myocytes and whether mitochondria are potential targets. Neonatal rat cardiac myocytes were cultured and subjected to oxidant stress (1 hour of 100 micromol/L H2O2). Mitochondrial membrane potential, a key determinant of cardiomyocyte viability, was assessed by flow cytometric analysis of tetramethylrhodamine ethyl ester (TMRE)-loaded cells. Hydrogen peroxide significantly reduced mitochondrial membrane potential. Incubation of the cardiac myocytes in simvastatin (> or =1 micromol/L) 1 hour before peroxide exposure significantly attenuated the loss of TMRE fluorescence. This effect was inhibited by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the ATP-sensitive mitochondrial potassium channel (mitoKATP) blocker 5-hydroxydecanoate. Simvastatin attenuates mitochondrial membrane depolarization after exposure to oxidant stress. These findings provide primary evidence that myocytes can act as triggers and effectors in the cardioprotective cascade of simvastatin therapy. These results bear implications of statin therapy as a potential clinical application of pharmacological preconditioning.
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D016877:Oxidants / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress; D015221:Potassium Channels; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D016877:Oxidants; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D019821:Simvastatin; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester