Cellular glutathione peroxidase deficiency and endothelial dysfunction.
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.
Forgione
Marc A
MA
Evans Department of Medicine, Boston, Massachusetts 02118, USA.
Weiss
Norbert
N
Heydrick
Stanley
S
Cap
André
A
Klings
Elizabeth S
ES
Bierl
Charlene
C
Eberhardt
Robert T
RT
Farber
Harrison W
HW
Loscalzo
Joseph
J
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
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