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

Abnormal regulation of local vascular tone occurs early in human and experimental atherosclerosis. Impaired endothelium-dependent vascular relaxations mediated by endothelium-derived relaxing factor are an important contributor to these abnormalities. Endothelium-derived relaxing factor is nitric oxide released as such or attached to a carrier molecule. Oxidized lipoproteins impede endothelium-derived relaxing factor-mediated responses in vitro. We designed in vivo experiments to determine whether hypercholesterolemia with and without deficiency of two endogenous lipid antioxidants, vitamin E and selenium, would result in endothelial dysfunction. Vitamin E and selenium deficiencies were induced in a group of hypertension-prone Dahl salt-sensitive rats fed a diet high in cholesterol (4%) but low in NaCl (0.5%) for 18 weeks. Two other groups of Dahl salt-sensitive rats received diets sufficient in vitamin E and selenium but containing either high or normal cholesterol levels (control group). Serum cholesterol levels increased approximately 10-fold in the two groups of rats fed high-cholesterol diets. Systolic blood pressure was 143+/-3 mm Hg in high-cholesterol/vitamin E- and selenium-sufficient rats and 142+/-5 mm Hg in high-cholesterol/vitamin E- and selenium-deficient rats (P=NS). Mild intimal thickening and occasional mononuclear cell infiltration were observed in both of these groups. Serum vitamin E levels were decreased, whereas serum thiobarbituric acid-reactive substances and exhaled pentane (two indicators of endogenous lipid oxidation) were significantly increased in high-cholesterol/vitamin E- and selenium-deficient rats compared with high-cholesterol/vitamin E- and selenium-sufficient rats. Vascular relaxations to acetylcholine and adenosine diphosphate, two agonists of endothelium-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 superoxide dismutase normalized relaxations in the impaired aortic rings. Relaxations in response to the endothelium-independent vasodilator sodium nitroprusside were normal in all three rat groups. Our findings indicate that hypercholesterolemia coexisting with increased levels of endogenous oxidants or deficient levels of antioxidants results in impaired endothelium-dependent vasodilation mediated by endothelium-derived relaxing factor.