title: Cellular glutathione peroxidase deficiency and endothelial dysfunction.
abstract: Cellular glutathione peroxidase (GPx-1) is the most abundant intracellular isoform of the GPx antioxidant enzyme family. In this study, we hypothesized that GPx-1 deficiency directly induces an increase in vascular oxidant stress, with resulting endothelial dysfunction. We studied vascular function in a murine model of homozygous deficiency of GPx-1 (GPx-1(-/-)). Mesenteric arterioles of GPx-1(-/-) mice demonstrated paradoxical vasoconstriction to beta-methacholine and bradykinin, whereas wild-type (WT) mice showed dose-dependent vasodilation in response to both agonists. One week of treatment of GPx-1(-/-) mice with L-2-oxothiazolidine-4-carboxylic acid (OTC), which increases intracellular thiol pools, resulted in restoration of normal vascular reactivity in the mesenteric bed of GPx-1(-/-) mice. We observed an increase of the isoprostane iPF(2alpha)-III, a marker of oxidant stress, in the plasma and aortas of GPx-1(-/-) mice compared with WT mice, which returned toward normal after OTC treatment. Aortic sections from GPx-1(-/-) mice showed increased binding of an anti-3-nitrotyrosine antibody in the absence of frank vascular lesions. These findings demonstrate that homozygous deficiency of GPx-1 leads to impaired endothelium-dependent vasodilator function presumably due to a decrease in bioavailable nitric oxide and to increased vascular oxidant stress. These vascular abnormalities can be attenuated by increasing bioavailable intracellular thiol pools.
authors.affiliation: Evans Department of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Forgione
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.forename: Stanley
authors.initials: S
authors.lastname: Heydrick
authors.forename: André
authors.initials: A
authors.lastname: Cap
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Klings
authors.forename: Charlene
authors.initials: C
authors.lastname: Bierl
authors.forename: Robert T
authors.initials: RT
authors.lastname: Eberhardt
authors.forename: Harrison W
authors.initials: HW
authors.lastname: Farber
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D013152:Splanchnic Circulation / Q000502:physiology
chemical_list: D016210:Methacholine Chloride; D009599:Nitroprusside; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006152:Cyclic GMP; D001920:Bradykinin