Cellular glutathione peroxidase deficiency and endothelial dysfunction
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 withl-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 2α-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.
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GPx-1-deficient mice manifest endothelial dysfunction, characterized by a lack of normal responses to endothelium-dependent vasoactive compounds.
“GPx-1-deficient mice manifest endothelial dysfunction, characterized by a lack of normal responses to endothelium-dependent vasoactive compounds (134, 135).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [135]
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- Authors
- Forgione, M. A., Weiss, N., Heydrick, S., Cap, A., Klings, E. S., Bierl, C., Eberhardt, R. T., Farber, H. W., & Loscalzo, J.
- Affiliations
- Evans Department of Medicine,
- Whitaker Cardiovascular Institute, Department of Pharmacology, and
- Boston University (US)
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2002-04-01
- Volume
- 282
- Issue
- 4
- Pages
- H1255-H1261
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2139527140
- Cited by
- 199
- References
- 41
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 11 · 2020: 5 · 2019: 10 · 2018: 3 · 2017: 9 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 9 · 2012: 10
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL61795, HL 55993, HL-07224-24, HL58976, R01HL058976, T32HL007224, P50HL055993)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
- Keywords
- glutathione peroxidase 1, endothelial dysfunction, mesenteric arterioles, endothelium-dependent vasodilation, nitric oxide bioavailability, nitrotyrosine, L-2-oxothiazolidine-4-carboxylic acid, bradykinin, aorta
- MeSH terms
- Animals, Bradykinin, Endothelium, Vascular, Glutathione Peroxidase, Cyclic GMP, Microcirculation, Nitroprusside, Splanchnic Circulation, Methacholine Chloride, Mice, Knockout, Oxidative Stress, Nitric Oxide Synthase, Models, Animal, Mice, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III
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