Heterozygous cellular glutathione peroxidase deficiency in the mouse

Abnormalities in vascular and cardiac function and structure

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

Research output: Contribution to journalArticle

145 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)1154-1158
Number of pages5
JournalCirculation
Volume106
Issue number9
DOIs
StatePublished - Aug 27 2002
Externally publishedYes

Fingerprint

Glutathione Peroxidase
Blood Vessels
Oxidants
Lipid Peroxides
Tunica Intima
Isoprostanes
Adventitia
Arterioles
Cardiovascular System
glutathione peroxidase GPX1
Vasoconstriction
Vasodilation
Hydrogen Peroxide
Acetylcholine
Reperfusion
Glutathione
Protein Isoforms
Ischemia
Fibroblasts
Antioxidants

Keywords

  • Antioxidants
  • Endothelium
  • Nitric oxide
  • Oxygen
  • Vasculature

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Forgione, M. A., Cap, A., Liao, R., Moldovan, N. I., Eberhardt, R. T., Lim, C. C., ... Loscalzo, J. (2002). Heterozygous cellular glutathione peroxidase deficiency in the mouse: Abnormalities in vascular and cardiac function and structure. Circulation, 106(9), 1154-1158. https://doi.org/10.1161/01.CIR.0000026820.87824.6A

Heterozygous cellular glutathione peroxidase deficiency in the mouse : Abnormalities in vascular and cardiac function and structure. / Forgione, Marc A.; Cap, Andre; Liao, Ronglih; Moldovan, Nicanor I.; Eberhardt, Robert T.; Lim, Chee Chew; Jones, John; Goldschmidt-Clermont, Pascal; Loscalzo, Joseph.

In: Circulation, Vol. 106, No. 9, 27.08.2002, p. 1154-1158.

Research output: Contribution to journalArticle

Forgione, MA, Cap, A, Liao, R, Moldovan, NI, Eberhardt, RT, Lim, CC, Jones, J, Goldschmidt-Clermont, P & Loscalzo, J 2002, 'Heterozygous cellular glutathione peroxidase deficiency in the mouse: Abnormalities in vascular and cardiac function and structure', Circulation, vol. 106, no. 9, pp. 1154-1158. https://doi.org/10.1161/01.CIR.0000026820.87824.6A
Forgione, Marc A. ; Cap, Andre ; Liao, Ronglih ; Moldovan, Nicanor I. ; Eberhardt, Robert T. ; Lim, Chee Chew ; Jones, John ; Goldschmidt-Clermont, Pascal ; Loscalzo, Joseph. / Heterozygous cellular glutathione peroxidase deficiency in the mouse : Abnormalities in vascular and cardiac function and structure. In: Circulation. 2002 ; Vol. 106, No. 9. pp. 1154-1158.
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AU - Liao, Ronglih

AU - Moldovan, Nicanor I.

AU - Eberhardt, Robert T.

AU - Lim, Chee Chew

AU - Jones, John

AU - Goldschmidt-Clermont, Pascal

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N2 - 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 iPF2α-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.

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