Cellular glutathione peroxidase deficiency and endothelial dysfunction

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 282; no. 4; pp. H1255 - H1261
• Main Authors: Forgione, Marc A, Weiss, Norbert, Heydrick, Stanley, Cap, Andre, Klings, Elizabeth S, Bierl, Charlene, Eberhardt, Robert T, Farber, Harrison W, Loscalzo, Joseph
• Format: Journal Article
• Language: English
• Published: United States 01.04.2002
• Subjects: 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
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00598.2001

1  Evans Department of Medicine, 2  Whitaker Cardiovascular Institute, Department of Pharmacology, and 3  Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118 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 -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 2 -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. nitric oxide; peroxynitrite; oxidant stress * M. A. Forgione and N. Weiss contributed equally to this work.