Role of hydrogen peroxide and the impact of glutathione peroxidase-1 in regulation of cerebral vascular tone.
Although arachidonic acid (AA) has diverse vascular effects, the mechanisms that mediate these effects are incompletely defined. The goal of our study was to use genetic approaches to examine the role of hydrogen peroxide (H2O2), glutathione peroxidase (Gpx1, which degrades H2O2), and CuZn-superoxide dismutase (SOD1, which produces H2O2 from superoxide) in mediating and in determining vascular responses to AA. In basilar arteries in vitro, AA produced dilation in nontransgenic mice, and this response was reduced markedly in transgenic mice overexpressing Gpx1 (Gpx1 Tg) or in those genetically deficient in SOD1. For example, AA (1 nmol/L to 1 mumol/L) dilated the basilar artery and this response was reduced by approximately 90% in Gpx1 Tg mice (P<0.01), although responses to acetylcholine were not altered. Dilation of cerebral arterioles in vivo in response to AA was inhibited by approximately 50% by treatment with catalase (300 U/mL) (P<0.05) and reduced by as much as 90% in Gpx1 Tg mice compared with that in controls (P<0.05). These results provide the first evidence that Gpx1 has functional effects in the cerebral circulation, and that AA-induced vascular effects are mediated by H2O2 produced by SOD1. In contrast, cerebral vascular responses to the endothelium-dependent agonist acetylcholine are not mediated by H2O2.
Department of Internal Medicine, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1081, USA.
Mary L
ML
Modrick
Sean P
SP
Didion
Cynthia M
CM
Lynch
Sanjana
S
Dayal
Steven R
SR
Lentz
Frank M
FM
Faraci
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014664:Vasodilation / Q000187:drug effects; D000094765:Glutathione Peroxidase GPX1
D016718:Arachidonic Acid; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D007213:Indomethacin; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse