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.


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 micromol/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.
Dayal
Sanjana
S
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Brown
Kara L
KL
Weydert
Christine J
CJ
Oberley
Larry W
LW
Arning
Erland
E
Bottiglieri
Teodoro
T
Faraci
Frank M
FM
Lentz
Steven R
SR
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D002339:Carotid Arteries / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D002374:Catalase / Q000378:metabolism; D004032:Diet; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000503:physiopathology*; D004996:Ethidium / Q000031:analogs & derivatives* / Q000032:analysis; D005979:Glutathione Peroxidase / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D008715:Methionine / Q000097:blood / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000032:analysis; D014666:Vasomotor System / Q000187:drug effects / Q000201:enzymology; D000094765:Glutathione Peroxidase GPX1
D006710:Homocysteine; C067883:dihydroethidium; D013481:Superoxides; D008715:Methionine; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D004996:Ethidium; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse