Mitochondrial-derived hydrogen peroxide inhibits relaxation of bovine coronary arterial smooth muscle to hypoxia through stimulation of ERK MAP kinase.
Mitochondrial reactive oxygen species (ROS) are potentially important in vascular oxygen-sensing mechanisms because hypoxia appears to be a stimulus for mitochondrial ROS generation; however, scavenging of endogenous ROS does not alter relaxation of endothelium-denuded bovine coronary arteries (BCA) to hypoxia. The purpose of this study was to investigate the influence of increasing mitochondrial ROS on the relaxation of BCA to hypoxia. Increasing mitochondrial superoxide with inhibitors of electron transport (10 microM rotenone and antimycin) and by opening mitochondrial ATP-dependent K+ channels with 100 microM diazoxide were observed in this study to attenuate relaxation of BCA precontracted with 30 mM KCl to hypoxia by 68-76% and 38%, respectively. This effect of rotenone is not prevented by inhibiting NADPH oxidase (Nox) activation or scavenging superoxide with Peg-SOD; however, it is reversed 85% and 26% by increasing the consumption of intracellular peroxide by 0.1 mM ebselen and 32.5 U/ml Peg-catalase. Because inhibition of extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase (10 microM PD-98059), but not src kinase or rho kinase, also reverses the effects of rotenone by 69%, the peroxide-elicited force-enhancing effects of ERK appear to be attenuating the response to hypoxia. Rotenone increased the phosphorylation of ERK (by 163%). Activation of ERK in BCA with 0.1 mM peroxide or endogenous peroxide generated by stimulating Nox2 with a stretch treatment or contraction with 100 nM U-46619 also attenuated relaxation to hypoxia. Thus coronary arterial relaxation to hypoxia may be attenuated by pathophysiological conditions associated with increased peroxide generation by mitochondria or other sources that stimulate ERK.
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
Qun
Q
Gao
Xiangmin
X
Zhao
Mansoor
M
Ahmad
Michael S
MS
Wolin
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002417:Cattle; D015687:Cell Hypoxia; D003331:Coronary Vessels / Q000201:enzymology; D004579:Electron Transport; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D066298:In Vitro Techniques; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000201:enzymology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000975:Antioxidants; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D014475:Uncoupling Agents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D013481:Superoxides; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D019061:src-Family Kinases; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases