Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction

• DOI: 10.1073/pnas.231428998
• Publication Date: 2002-07-26T14:34:10Z
• Authors: Norbert Weiss; Ying-Yi Zhang; Stanley Heydrick; Charlene Bierl; Joseph Loscalzo
• Keywords: GPX1; Endothelial Dysfunction

Homocyst(e)ine (Hcy) inhibits the expression of antioxidant enzyme cellular glutathione peroxidase (GPx-1) in vitro and vivo , which can lead to an increase reactive oxygen species that inactivate NO promote endothelial dysfunction. In this study, we tested hypothesis overexpression GPx-1 restore normal phenotype hyperhomocyst(e)inemic states. Heterozygous cystathionine β-synthase-deficient (CBS (−/+) ) mice their wild-type littermates (+/+) were crossbred with overexpress [GPx-1 (tg+) mice]. activity was 28% lower CBS /GPx-1 (tg−) compared ( P < 0.05), overexpressing had 1.5-fold higher nontransgenic 0.05). Mesenteric arterioles showed vasoconstriction superfusion β-methacholine bradykinin 0.001 vs. all other groups), whereas nonhyperhomocyst(e)inemic [CBS mice] demonstrated dose-dependent vasodilation response both agonists. Overexpression restored endothelium-dependent vasodilator response. Bovine aortic cells (BAEC) transiently transfected incubated dl -homocysteine (HcyH) or l -cysteine. HcyH incubation decreased sham-transfected BAEC 0.005) but not GPx-1-transfected cells. Nitric oxide release from significantly by cysteine, attenuated decrease. These findings demonstrate compensate for adverse effects Hcy on function suggest vascular are at least partly mediated oxidative inactivation NO.