Heterozygous cellular glutathione peroxidase deficiency in the mouse: abnormalities in vascular and cardiac function and structure

Circulation. 2002 Aug 27;106(9):1154-8. doi: 10.1161/01.cir.0000026820.87824.6a.

Abstract

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 iPF(2alpha)-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Aorta, Thoracic / chemistry
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / pathology
  • Bradykinin / pharmacology
  • Coronary Vessels / pathology
  • Cyclic GMP / analysis
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Targeting
  • Glutathione Peroxidase / deficiency*
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase GPX1
  • Heterozygote
  • In Vitro Techniques
  • Male
  • Mesentery / blood supply
  • Mesentery / physiopathology*
  • Metabolism, Inborn Errors / genetics
  • Metabolism, Inborn Errors / pathology
  • Metabolism, Inborn Errors / physiopathology*
  • Mice
  • Microcirculation / drug effects
  • Muscarinic Agonists / pharmacology
  • Myocardial Contraction* / drug effects
  • Myocardial Contraction* / genetics
  • Myocardium / metabolism
  • Myocardium / pathology
  • Nitric Oxide Donors / pharmacology
  • Oxidative Stress
  • Vasodilator Agents / pharmacology
  • Vasomotor System / drug effects
  • Vasomotor System / physiopathology*

Substances

  • Antioxidants
  • Muscarinic Agonists
  • Nitric Oxide Donors
  • Vasodilator Agents
  • Glutathione Peroxidase
  • Cyclic GMP
  • Bradykinin
  • Glutathione Peroxidase GPX1
  • Gpx1 protein, mouse