Heterozygous cellular glutathione peroxidase deficiency in the mouse - Abnormalities in vascular and cardiac function and structure

被引:169
作者
Forgione, MA
Cap, A
Liao, R
Moldovan, NI
Eberhardt, RT
Lim, CC
Jones, J
Goldschmidt-Clermont, PJ
Loscalzo, J
机构
[1] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Dept Surg, Boston, MA 02118 USA
[3] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA
[4] Ohio State Univ, Dept Med, Cardiol Sect, Columbus, OH 43210 USA
[5] Duke Univ, Sch Med, Durham, NC USA
关键词
endothelium; vasculature; antioxidants; oxygen; nitric oxide;
D O I
10.1161/01.CIR.0000026820.87824.6A
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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- I (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 mug/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.
引用
收藏
页码:1154 / 1158
页数:5
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