Induction of hepatic inducible nitric oxide synthase by cholesterol in vivo and in vitro

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 highfat-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.

The Effects of Capsaicin and Vitamine E on High Fat Diet Induced Obesity, Hyperlipidemia and Oxidative Stress in Different Organs of Mice

“…Similarly, in our study high fat diets affected NO production in all organ tissues. Inducible nitric oxide synthase (iNOS) mRNA and protein activity have also been found to be induced in rats on a high-fat diet [43]. In parallel to our findings, alpha-tocopherol induced nitric oxide synthase activity in blood vessels [44] and in penile tissue [45] of rats were also demonstrated.…”

Consumption of dried fruit of Crataegus pinnatifida (hawthorn) suppresses high-cholesterol diet-induced hypercholesterolemia in rats

“…Thus, it is not surprising to observe an increase in the activity of NOS (presumably iNOS which participates in inflammation responses) of the liver (but not kidneys) in HCD-fed rats, as described elsewhere (Kim et al, 2002). Perhaps, the inflammation associated with HCD is resulted from an attenuated level of hepatic anti-oxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) as clearly illustrated in our study.…”

Ligustrazine improves atherosclerosis in rat via attenuation of oxidative stress

“…Human investigations also support the oxidative stress hypothesis of atherosclerosis (Soccio et al, 2005). In response to oxidative stress, the vascular antioxidant system was activated in atherosclerotic lesions (Kobayashi et al, 2002) and in the liver (Kim et al, 2002). Coincided with the previous reports, we found the genes encoding the master regulator in the antioxidant system, pgc-1α (St-Pierre et al, 2006), and three antioxidant enzymes (sod1, catalase, and gpx-1) were all induced in aorta and in liver of atherosclerotic rats, together with the decreased T-AOC in the plasma, suggesting the burdened oxidative stress.…”