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Cholesterol-rich diet impairs endothelial NO syn-thase (eNOS) and enhances inducible NOS (iNOS)expresion. In this study, we investigated efects ofcholesterol on iNOS expression in high-fat-fed ratmodels, HepG2 and RAW264.7 cels. The high-fatdiet increased the plasma total cholesterol level 6-7fold and low-density lipoprotein cholesterol level(LDL-C) approximately 70 fold and slightly increasedthe level of lipid peroxidation as determined bythiobarbituric acid-reactive substance assay. Thehigh-fat diet also increased plasma nitric oxide (NO)concentrations up to 5 fold, and induced iNOSmRNA expression in liver. The contractile responsesof the endothelium-denuded thoracic aortic rings tophenylephrine were significantly damaged in high-fat-fed rats when assessed by organ chamber study.Treatment with estrogen for 4 days failed to reduceiNOS expresions as well as aortic contractility,although it improved lipid profiles. In culturedHepG2 or murine macrophage RAW264.7 cells, 3days treatment with either 25-hydroxycholesterol or7-ketocholesterol induced iNOS mRNA expression,as determined by RT-PCR. Our data suggested thatthe chronic exposure of hepatocytes and macroph-age cells to high concentration of cholesterol oroxysterols may induce iNOS expression and subse-quent synthesis of NO, which may be important inthe pathogenesis of atherosclerosis.

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