HYPERCHOLESTEROLEMIA PROMOTES ENDOTHELIAL DYSFUNCTION IN VITAMIN-E-DEFICIENT AND SELENIUM-DEFICIENT RATS

Abnormal regulation of local vascular tone occurs early in human and e xperimental atherosclerosis. Impaired endothelium-dependent vascular r elaxations mediated by endothelium-derived relaxing factor are an impo rtant contributor to these abnormalities. Endothelium-derived relaxing factor is nitric oxide released as such or attached to a carrier mole cule. Oxidized lipoproteins impede endothelium-derived relaxing factor -mediated responses in vitro. We designed in vivo experiments to deter mine whether hypercholesterolemia with and without deficiency of two e ndogenous lipid antioxidants, vitamin E and selenium, would result in endothelial dysfunction. Vitamin E and selenium deficiencies were indu ced in a group of hypertension-prone Dahl salt-sensitive rats fed a di et high in cholesterol (4%) but low in NaCl (0.5%) for 18 weeks. Two o ther groups of Dahl salt-sensitive rats received diets sufficient in v itamin E and selenium but containing either high or normal cholesterol levels (control group). Serum cholesterol levels increased approximat ely 10-fold in the two groups of rats fed high-cholesterol diets. Syst olic blood pressure was 143+/-3 mm Hg in high-cholesterol/vitamin E- a nd selenium-sufficient rats and 142+/-5 mm Hg in high-cholesterol/vita min E- and selenium-deficient rats (P=NS). Mild intimal thickening and occasional mononuclear cell infiltration were observed in both of the se groups. Serum vitamin E levels were decreased, whereas serum thioba rbituric acid-reactive substances and exhaled pentane (two indicators of endogenous lipid oxidation) were significantly increased in high-ch olesterol/vitamin E- and selenium-deficient rats compared with high-ch olesterol/vitamin E- and selenium-sufficient rats. Vascular relaxation s to acetylcholine and adenosine diphosphate, two agonists of endothel ium-dependent relaxations, were significantly impaired in aortic rings from only the high-cholesterol/vitamin E- and selenium-deficient rats . Neither indomethacin nor the scavenger of superoxide anion superoxid e dismutase normalized relaxations in the impaired aortic rings. Relax ations in response to the endothelium-independent vasodilator sodium n itroprusside were normal in all three rat groups. Our findings indicat e that hypercholesterolemia coexisting with increased levels of endoge nous oxidants or deficient levels of antioxidants results in impaired endothelium-dependent vasodilation mediated by endothelium-derived rel axing factor.