PMID:11893559

Citation	Forgione, MA, Weiss, N, Heydrick, S, Cap, A, Klings, ES, Bierl, C, Eberhardt, RT, Farber, HW and Loscalzo, J (2002) Cellular glutathione peroxidase deficiency and endothelial dysfunction. Am. J. Physiol. Heart Circ. Physiol. 282:H1255-61
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.
Links	PubMed Online version:10.1152/ajpheart.00598.2001
Keywords	Animals; Bradykinin/pharmacology; Cyclic GMP/metabolism; Endothelium, Vascular/physiopathology; Glutathione Peroxidase/deficiency; Glutathione Peroxidase/genetics; Glutathione Peroxidase/metabolism; Methacholine Chloride/pharmacology; Mice; Mice, Knockout; Microcirculation/drug effects; Microcirculation/physiology; Models, Animal; Nitric Oxide Synthase/genetics; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroprusside/pharmacology; Oxidative Stress/physiology; Splanchnic Circulation/physiology
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