Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase

被引:580
作者
Upchurch, GR
Welch, GN
Fabian, AJ
Freedman, JE
Johnson, JL
Keaney, JF
Loscalzo, J
机构
[1] BOSTON UNIV,SCH MED,WHITAKER CARDIOVASC INST,BOSTON,MA 02118
[2] BOSTON UNIV,SCH MED,EVANS DEPT MED,BOSTON,MA 02118
[3] HARVARD UNIV,BRIGHAM & WOMENS HOSP,SCH MED,DEPT SURG,BOSTON,MA 02115
关键词
D O I
10.1074/jbc.272.27.17012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hyperhomocyst(e)inemia is believed to injure endothelial cells in vivo through a number of mechanisms, including the generation of hydrogen peroxide (H2O2), Earlier in vitro studies demonstrated that homocyst(e)ine (Hcy) decreases the biological activity of endothelium-derived relaxing factor and that this decrease can be reversed by preventing the generation of hydrogen peroxide, Here we show that Hcy treatment of bovine aortic endothelial cells leads to a dose-dependent decrease in NOx (p = 0.001 by one-way analysis of variance) independent of endothelial nitric-oxide synthase activity or protein levels and nos3 transcription, suggesting that Hcy affects the bioavailability of NO, not its production, We hypothesized that, in addition to increasing the generation of H2O2, Hcy decreases the cell's ability to detoxify H2O2 by impairing intracellular antioxidant enzymes, specifically the intracellular isoform of glutathione peroxidase (GPx), To test this hypothesis, confluent bovine aortic endothelial cells were treated with a range of concentrations of Hcy, and intracellular GPx activity was determined, Compared with control cells, cells treated with Hcy showed a significant reduction in GPx activity (up to 81% at 250 mu M Hcy), In parallel with the decrease in GPx activity, steady-state GPx mRNA levels were also significantly decreased compared with control levels after exposure to Hcy, which appeared not to be a consequence of message destabilization, These data suggest; a novel mechanism by which Hcy, in addition to increasing the generation of hydrogen peroxide, may selectively impair the endothelial cells ability to detoxify H2O2, thus rendering NO more susceptible to oxidative inactivation.
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页码:17012 / 17017
页数:6
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