Published Online
on August 5, 2002

A more recent version of this article appeared on August 27, 2002

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Submitted on April 29, 2002
Revised on May 31, 2002
Accepted on June 3, 2002

Heterozygous Cellular Glutathione Peroxidase Deficiency in the Mouse. Abnormalities in Vascular and Cardiac Function and Structure

Marc A. Forgione MD, Andre Cap PhD, Ronglih Liao PhD, Nicanor I. Moldovan PhD, Robert T. Eberhardt MD, Chee Chew Lim PhD, John Jones MD, Pascal J. Goldschmidt-Clermont MD, and Joseph Loscalzo MD, PhD^*

From Evans Department of Medicine (M.A.F., R.L., R.T.E., C.C.L., J.L.), Department of Surgery (J.J.), and Whitaker Cardiovascular Institute (M.A.F., A.C., R.L., C.C.L., R.T.E., J.J., J.L.), Boston University School of Medicine, Boston, Mass; Cardiology Section, Department of Medicine (N.M.), The Ohio State University, Columbus, Ohio; and Duke University School of Medicine (P.G.), Durham, NC.

^* To whom correspondence should be addressed. E-mail: jloscalz{at}bu.edu.

Background—Oxidant stress has been implicated in the pathogenesis of atherothrombosis and other vascular disorders accompanied by endothelial dysfunction. Glutathione peroxidases (GPx) play an important role in the cellular defense against oxidant stress by utilizing glutathione (GSH) to reduce lipid hydroperoxides and hydrogen peroxide to their corresponding alcohols. Cellular GPx (GPx-1) is the principal intracellular isoform of GPx. We hypothesized that GPx-1 deficiency per se induces endothelial dysfunction and structural vascular abnormalities through increased oxidant stress.

Methods and Results—A murine model of heterozygous deficiency of GPx-1 (GPx^+/-) was investigated to examine this hypothesis. Mesenteric arterioles in GPx-1^+/- mice demonstrated vasoconstriction to acetylcholine compared with vasodilation in wild-type mice (maximal change in vessel diameter, -13.0±2.8% versus 13.2±2.8%, P<0.0001). We also noted an increase in the plasma and aortic levels of the isoprostane iPF₂-III, a marker of oxidant stress, in GPx-1^+/- mice compared with wild-type mice (170.4±23 pg/mL plasma versus 98.7±7.1 pg/mL plasma, P<0.03; 11.7±0.87 pg/mg aortic tissue versus 8.2±0.55 pg/mg aortic tissue, P<0.01). Histological sections from the coronary vasculature of GPx-1^+/- mice show increased perivascular matrix deposition, an increase in the number of adventitial fibroblasts, and intimal thickening. These structural abnormalities in the myocardial vasculature were accompanied by diastolic dysfunction after ischemia-reperfusion.

Conclusions—These findings demonstrate that heterozygous deficiency of GPx-1 leads to endothelial dysfunction, possibly associated with increased oxidant stress, and to significant structural vascular and cardiac abnormalities. These data illustrate the importance of this key antioxidant enzyme in functional and structural responses of the mammalian cardiovascular system.

Key words: endothelium • vasculature • antioxidants • oxygen • nitric oxide

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