Glutathione peroxidase-1 plays a major role in protecting against angiotensin II-induced vascular dysfunction.
Levels of reactive oxygen species, including hydrogen peroxide(,) increase in blood vessels during hypertension and in response to angiotensin II (Ang II). Although glutathione peroxidases are known to metabolize hydrogen peroxide, the role of glutathione peroxidase during hypertension is poorly defined. We tested the hypothesis that glutathione peroxidase-1 protects against Ang II-induced endothelial dysfunction. Responses of carotid arteries from Gpx1-deficient (Gpx1(+/-) and Gpx1(-/-)) and Gpx1 transgenic mice, and their respective littermate controls, were examined in vitro after overnight incubation with either vehicle or Ang II. Under control conditions, relaxation to acetylcholine (ACh; an endothelium-dependent agonist) was similar in control, Gpx1(+/-), and Gpx1 transgenic mice, whereas in Gpx1(-/-) mice, responses to ACh were impaired. In control mice, ACh-induced vasorelaxation was not affected by 1 nmol/L of Ang II. In contrast, relaxation to ACh in arteries from Gpx1(+/-) mice was inhibited by approximately 60% after treatment with 1 nmol/L of Ang II, indicating that Gpx1 haploinsufficiency markedly enhances Ang II-induced endothelial dysfunction. A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to ACh in arteries from control mice, and this effect was prevented in arteries from Gpx1 transgenic mice or in arteries from control mice treated with polyethylene glycol-catalase (which degrades hydrogen peroxide). Thus, genetic and pharmacological evidence suggests a major role for glutathione peroxidase-1 and hydrogen peroxide in Ang II-induced effects on vascular function.
Chrissobolis
Sophocles
S
Department of Internal Medicine, Cardiovascular Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242-1081, USA.
Didion
Sean P
SP
Kinzenbaw
Dale A
DA
Schrader
Laura I
LI
Dayal
Sanjana
S
Lentz
Steven R
SR
Faraci
Frank M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology; D002374:Catalase / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000502:physiology; D011092:Polyethylene Glycols / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D000094765:Glutathione Peroxidase GPX1
D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C070295:catalase-polyethylene glycol; D000804:Angiotensin II; D011092:Polyethylene Glycols; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; D000109:Acetylcholine; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse