Deficiency of glutathione peroxidase-1 sensitizes hyperhomocysteinemic mice to endothelial dysfunction.

Objective-We tested the hypothesis that deficiency of cellular glutathione peroxidase (GPx-1) enhances susceptibility to endothelial dysfunction in mice with moderate hyperhomocysteinemia. Methods and Results-Mice that were wild type (Gpx1(+/+)), heterozygous (Gpx1(+/-)), or homozygous (Gpx1(-/-)) for the mutated Gpx1 allele were fed a control diet or a high-methionine diet for 17 weeks. Plasma total homocysteine was elevated in mice on the high-methionine diet compared with mice on the control diet (23+/-3 versus 6+/-0.3 mumol/L, respectively; P<0.001) and was not influenced by Gpx1 genotype. In mice fed the control diet, maximal relaxation of the aorta in response to the endothelium-dependent dilator acetylcholine (10(-5) mol/L) was similar in Gpx1(+/+), Gpx1(+/-), and Gpx1(-/-) mice, but relaxation to lower concentrations of acetylcholine was selectively impaired in Gpx1(-/-) mice (P<0.05 versus Gpx1(+/+) mice). In mice fed the high-methionine diet, relaxation to low and high concentrations of acetylcholine was impaired in Gpx1(-/-) mice (maximal relaxation 73+/-6% in Gpx1(-/-) mice versus 90+/-2% in Gpx1(+/+) mice, P<0.05). No differences in vasorelaxation to nitroprusside or papaverine were observed between Gpx1(+/+) and Gpx1(-/-) mice fed either diet. Dihydroethidium fluorescence, a marker of superoxide, was elevated in Gpx1(-/-) mice fed the high-methionine diet (P<0.05 versus Gpx1(+/+) mice fed the control diet). Conclusions-These findings demonstrate that deficiency of GPx-1 exacerbates endothelial dysfunction in hyperhomocysteinemic mice and provide support for the hypothesis that hyperhomocysteinemia contributes to endothelial dysfunction through a peroxide-dependent oxidative mechanism.