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Am J Physiol Heart Circ Physiol 282: H1255-H1261, 2002. First published December 6, 2001; doi:10.1152/ajpheart.00598.2001
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Vol. 282, Issue 4, H1255-H1261, April 2002

Cellular glutathione peroxidase deficiency and endothelial dysfunction

Marc A. Forgione1,2,*, Norbert Weiss2,*, Stanley Heydrick2, André Cap2, Elizabeth S. Klings1,3, Charlene Bierl2, Robert T. Eberhardt1,2, Harrison W. Farber1,3, and Joseph Loscalzo1,2

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 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 iPF2alpha -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.




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