Glutathione Peroxidase-1 Plays a Major Role in Protecting Against Angiotensin II–Induced Vascular Dysfunction

Abstract

Abstract-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 ϩ/Ϫ and Gpx1 Ϫ/Ϫ ) 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 ϩ/Ϫ , and Gpx1 transgenic mice, whereas in Gpx1 Ϫ/Ϫ 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 ϩ/Ϫ mice was inhibited by Ϸ60% 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. (Hypertension. 2008;51:872-877.)

An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress

“…The concomitant hypertrophy in αCGRPKOs and loss of increased GPX-1 gene expression at 28 days is in keeping with studies using GPX-1 KO mice which revealed protection against AngII-induced artery functional and cardiac remodeling changes. 37,39 We provide novel evidence linking αCGRP with vascular protection against enhanced oxidative stress in a model of hypertension, consistent with evidence from cardiac models 8,40 and an atherosclerosis model. 41 We further provide evidence of enhanced ROS generation in αCGRPKO-AngII mice at day 28, as shown recently in a wire-induced vascular injury model.…”

Glutathione Peroxidase-1 Deficiency Potentiates Dysregulatory Modifications of Endothelial Nitric Oxide Synthase and Vascular Dysfunction in Aging

“…6 Previous studies have revealed increased mitochondrial and systemic oxidative stress in glutathione peroxidase-1 (GPx-1)-ablated mice 7 and synergistic negative effects on vascular function in the setting of hyperlipidemia, 8 diabetes mellitus, 9 and hypertension. 10 Moreover, increased senescence was demonstrated for fibroblasts from GPx-1 −/− mice. 7 Most importantly, a correlation between GPx-1 activity in blood cells and…”

Selenium supplementation does not improve vascular responsiveness in healthy North American men

“…Mesenteric arterioles from mice heterozygous (26) or homozygous (27) for deletion of the GPX1 gene exhibited paradoxical vasoconstriction in response to acetylcholine or ␤-methacholine, respectively, instead of the normal vasodilation observed in wild-type mice. Relaxation to acetylcholine was markedly impaired in angiotensin II-treated carotid arteries from GPX ϩ/Ϫ transgenic mice (14) and in untreated carotid arteries from homocysteine-treated GPX Ϫ/Ϫ transgenic mice (18). Moreover, the overexpression of GPX1 restored the normal endothelium-dependent vasodilator response in hyperhomocysteinemic mice (66).…”