Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice.
ABSTRACT The inducible nitric oxide synthase (iNOS) is abundantly expressed by smooth muscle cells and macrophages in atherosclerotic lesions. Apolipoprotein E-deficient (apoE(-/-)) mice develop early and advanced atherosclerotic lesions. The role of iNOS in both early and advanced atherosclerotic formation was determined in apoE(-/-) mice. Mice were fed chow or a Western diet containing 42% fat, 0.15% cholesterol, and 19.5% casein. At 12 weeks of age on chow diet, iNOS(-/-)/apoE(-/-) mice developed comparable sizes of early atherosclerotic lesions in the aortic root as did iNOS(+/+)/apoE(-/-) mice (30,993+/-4746 vs. 26,648+/-6815 microm(2)/section; P=0.608). After being fed the Western diet for 12 weeks, iNOS(-/-)/apoE(-/-) mice developed significantly smaller advanced lesions than iNOS(+/+)/apoE(-/-) mice (458,734+/-14,942 vs. 519,570+/-22,098 microm(2)/section; P=0.029). This reduction in lesion formation could not be explained by differences in plasma lipid levels. To examine whether iNOS contributed to LDL oxidation, smooth muscle cells were isolated from the aorta, activated with TNF-alpha, and then incubated with native LDL in the absence or presence of N-Omega-nitro-L-arginine methyl ester (L-NAME), a specific NOS inhibitor. L-NAME significantly inhibited LDL oxidation by smooth muscle cells from iNOS(+/+)/apoE(-/-) mice (P=0.048), but it had no effect on LDL oxidation by cells from iNOS(-/-)/apoE(-/-) mice. iNOS(-/-)/apoE(-/-) mice had a significantly lower plasma lipoperoxide level on the Western diet (2.74+/-0.23 vs. 3.89+/-0.41 microM MDA; P=0.021) but not on chow diet (1.02+/-0.07 vs. 1.51+/-0.29 microM MDA; P=0.11). Thus, the absence of iNOS-mediated LDL oxidation may contribute to the reduction in advanced lesion formation of iNOS(-/-)/apoE(-/-) mice.
Article: L-arginine supplementation influenced nitrite but not nitrate and total nitrite in rabbit model of hypercholesterolemia.[show abstract] [hide abstract]
ABSTRACT: The assessment of altered nitric oxide (NO) availability is of potentially important diagnostic and prognostic significance. The present study is aimed to investigate the effect of L-arginine (as a natural NO donor) supplementation on NO metabolite in a rabbit model of hypercholesterolemia to find a reliable marker for endothelial NO production. White male rabbits (n = 30) randomly assigned to 2 groups. Rabbits were fed 1% high-cholesterol diet (HC group, n = 15), or HC diet with oral L-arginine (3% in drinking water) (HC + L-arginine group, n = 15) for 4 weeks. The serum levels of lipids, L-arginine, total NO metabolites (NOx), nitrite and nitrate were measured before and after the study. In this study, L-arginine supplementation led to a significant increased plasma level of L-arginine. The serum level of nitrite was significantly higher in L-arginine treated group while serum level of nitrate and NOx was significantly lower than HC group. As the result of our study showed, nitrite is a useful marker of endogenous endothelial NO production and although frequently used, neither nitrate nor NOx are reliable markers of acute changes in endothelial NO synthase activity.Iranian biomedical journal 08/2008; 12(3):179-84.
Article: Foxo1 links hyperglycemia to LDL oxidation and endothelial nitric oxide synthase dysfunction in vascular endothelial cells.[show abstract] [hide abstract]
ABSTRACT: Atherosclerotic cardiovascular disease is the leading cause of death among people with diabetes. Generation of oxidized LDLs and reduced nitric oxide (NO) availability because of endothelial NO synthase (eNOS) dysfunction are critical events in atherosclerotic plaque formation. Biochemical mechanism leading from hyperglycemia to oxLDL formation and eNOS dysfunction is unknown. We show that glucose, acting through oxidative stress, activates the transcription factor Foxo1 in vascular endothelial cells. Foxo1 promotes inducible NOS (iNOS)-dependent NO-peroxynitrite generation, which leads in turn to LDL oxidation and eNOS dysfunction. We demonstrate that Foxo1 gain-of-function mimics the effects of hyperglycemia on this process, whereas conditional Foxo1 knockout in vascular endothelial cells prevents it. The findings reveal a hitherto unsuspected role of the endothelial iNOS-NO-peroxynitrite pathway in lipid peroxidation and eNOS dysfunction and suggest that Foxo1 activation in response to hyperglycemia brings about proatherogenic changes in vascular endothelial cell function.Diabetes 08/2009; 58(10):2344-54. · 8.29 Impact Factor