Cellular glutathione peroxidase deficiency and endothelial dysfunction

Marc A. Forgione, Norbert Weiss, Stanley Heydrick, André Cap, Elizabeth S. Klings, Charlene Bierl, Robert T. Eberhardt, Harrison W. Farber, Joseph Loscalzo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

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 β-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-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.

Original languageEnglish
Pages (from-to)H1255-H1261
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume282
Issue number4 51-4
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Nitric oxide
  • Oxidant stress
  • Peroxynitrite

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