[Effect of HMG-CoA reductase inhibition on endothelial dysfunction-inducing protein in hypercholesterolemic rabbits].

INTRODUCTION AND OBJECTIVES In our laboratory, we recently obtained evidence that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-unstranslated region of endothelial nitric oxide synthase (eNOS) mRNA and are associated with its destabilization. The aim of this study was to determine the presence of such proteins and the level of eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction. METHODS AND RESULTS Endothelium-dependent relaxation in response to acetylcholine was reduced in aortic segments from hypercholesterolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with simvastatin (25 mg/kg body weight/day) restored endothelium-dependent relaxation. Aortic eNOS expression was reduced in hypercholesterolemic rabbits and was accompanied by enhanced binding activity of a 60-KDa cytosolic protein and reduced stability of eNOS mRNA. Simvastatin treatment upregulated eNOS expression and reduced the interaction of cytosolic protein with the 3'-untranslated region of eNOS mRNA. CONCLUSIONS These results demonstrate the presence of a 60-KDa protein that binds to eNOS mRNA and reduces eNOS expression in the vascular wall.