TY - JOUR
T1 - Heterozygous cellular glutathione peroxidase deficiency in the mouse
T2 - Abnormalities in vascular and cardiac function and structure
AU - Forgione, Marc A.
AU - Cap, Andre
AU - Liao, Ronglih
AU - Moldovan, Nicanor I.
AU - Eberhardt, Robert T.
AU - Lim, Chee Chew
AU - Jones, John
AU - Goldschmidt-Clermont, Pascal J.
AU - Loscalzo, Joseph
PY - 2002/8/27
Y1 - 2002/8/27
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.
AB - 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.
KW - Antioxidants
KW - Endothelium
KW - Nitric oxide
KW - Oxygen
KW - Vasculature
UR - http://www.scopus.com/inward/record.url?scp=0037183563&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.0000026820.87824.6A
DO - 10.1161/01.CIR.0000026820.87824.6A
M3 - Article
C2 - 12196344
AN - SCOPUS:0037183563
SN - 0009-7322
VL - 106
SP - 1154
EP - 1158
JO - Circulation
JF - Circulation
IS - 9
ER -