Regulation of endothelial nitric oxide synthase expression in the vascularwall and in mononuclear cells from hypercholesterolemic rabbits

Background-We recently obtained evidence demonstrating that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3 ' -untranslated region of endothelial nitric oxide synthase (eNOS) mRNA a nd are associated with its destabilization. The aim of this study was to de termine the presence of such proteins and eNOS expression in hypercholester olemic rabbits as an in vivo model of endothelial dysfunction. Methods and Results-Endothelium-dependent relaxation to acetylcholine and t he calcium ionophore A23187 was reduced in aortic segments from hypercholes terolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with cerivastatin (0.1 mg . kg body wt(-1) . d(-1)) restored endot helium-dependent relaxation. Aortic eNOS expression was reduced in hypercho lesterolemic rabbits and was accompanied by enhanced binding activity of a 60-kDa cytosolic protein and reduced stability of eNOS mRNA. Cerivastatin t reatment upregulated eNOS expression and reduced the interaction of the cyt osolic protein with the 3 ' -untranslated region of eNOS mRNA. Mononuclear cells from hypercholesterolemic rabbits also showed a marked reduction of e NOS expression and eNOS mRNA stability and an increase in binding activity of the cytosolic protein, which were also prevented by cerivastatin treatme nt. Conclusions-These results demonstrate the presence of a 60-kDa protein that binds to eNOS mRNA and reductions in eNOS expression in both vascular wall and mononuclear cells that are prevented by cerivastatin.