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Abstract
Cholesterol-rich diet impairs endothelial NO synthase (eNOS) and enhances inducible NOS (iNOS) expression. In this study, we investigated effects of cholesterol on iNOS expression in high-fat-fed rat models, HepG2 and RAW264.7 cells. The high-fat diet increased the plasma total cholesterol level 6-7 fold and low-density lipoprotein cholesterol level (LDL-C) approximately 70 fold and slightly increased the level of lipid peroxidation as determined by thiobarbituric acid-reactive substance assay. The high-fat diet also increased plasma nitric oxide (NO) concentrations up to 5 fold, and induced iNOS mRNA expression in liver. The contractile responses of the endothelium-denuded thoracic aortic rings to phenylephrine were significantly damaged in high-fat-fed rats when assessed by organ chamber study. Treatment with estrogen for 4 days failed to reduce iNOS expressions as well as aortic contractility, although it improved lipid profiles. In cultured HepG2 or murine macrophage RAW264.7 cells, 3 days treatment with either 25-hydroxycholesterol or 7-ketocholesterol induced iNOS mRNA expression, as determined by RT-PCR. Our data suggested that the chronic exposure of hepatocytes and macrophage cells to high concentration of cholesterol or oxysterols may induce iNOS expression and subsequent synthesis of NO, which may be important in the pathogenesis of atherosclerosis.
Highlights
Nitric oxide (NO), which is a short-lived free radical, important signaling molecule and potent vasodilator (Ignarro et al, 1987), influences physiological processes in every organ and tissue (Li and Billiar, 1999)
Total C: total cholesterol, LDL cholesterol (LDL-C): low density lipoprotein cholesterol, Thiobarbituric acid-reactive substances (TBARS): thiobarbituric acid reactive substances, N, normal diet group; NE, normal diet group treated with 17αethinyl estradiol (EE, 10 mg/kg per day, s.c) for 4 consecutive days; HF, highfat diet group; HE, high fat diet group injected with EE as NE
Hypercholesterolemia is known to be associated with an impaired endothelial nitric oxide (NO) production and consequent alteration in endothelial NO synthase (eNOS) abundance and activity has been proposed to constitute early events in the development of atherosclerosis (Feron et al, 1999), there are few reports on the inducible NOS (iNOS) expression
Summary
Nitric oxide (NO), which is a short-lived free radical, important signaling molecule and potent vasodilator (Ignarro et al, 1987), influences physiological processes in every organ and tissue (Li and Billiar, 1999). It exhibits a remarkably wide spectrum of functions, including roles in neurotransmission and memory formation, prevention of blood clotting, regulation of blood pressure, and mediation of the bactericidal and tumoricidal activity of macrophages (Nathan and Hibbs, 1991). The biological functions of individual NOS have been clarified by the use of various NOS-knockout mice. nNOS KO mice were resistant to brain damage caused by vascular strokes, showing nNOS is crucial in mediating stroke damage (Nelson et al, 1995). eNOS KO mice demonstrated the involvement of eNOS in normal blood pressure regulation since their aortic rings displayed no relaxation in response to acetylcholine and their mean arterial blood pressures
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