Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induced expression of vascular cell adhesion molecule-1 (VCAM-1) and of nitric oxide synthase (iNOS) is believed to play a role in the pathogenesis of atherosclerosis, asthma, as well as other inflammatory disorders. In the current study we examined the effect of the di-catechol rooperol [(E)-1,5-bis (3',4'-dihydroxyphenyl) pent-4-en-1-yne] on the process of microvascular endothelial cell (MME) activation by TNF-alpha and IFN-gamma. We show that rooperol decreases VCAM-1 and iNOS mRNA levels in cytokine-activated MME with subsequent inhibition of VCAM-1 membrane expression as measured by adhesion of P815 cells to MME monolayers, and NO production, as reflected in the nitrite concentration in culture medium. The properties of rooperol now described suggest that rooperol may be an anti-inflammatory agent useful in the treatment of several inflammatory disorders.
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PMID:Inhibitory effect of di-catechol rooperol on VCAM-1 and iNOS expression in cytokine-stimulated endothelium. 901 Apr 88

L-arginine is the physiological precursor of nitric oxide (NO) which is formed in endothelial cells by the activity of the constitutive NO synthase isoenzyme. NO is tonically released from the endothelium, thus maintaining an active vasodilator tone and inhibiting platelet aggregation, leukocyte adhesion, and vascular smooth muscle cell proliferation. In experimental hypercholesterolemia and atherosclerosis as well as in hypercholesterolemic patients, NO-mediated responses have been shown to be impaired. Whether decreased formation and/or enhanced oxidative inactivation are involved in this process, is still unclear. Chronic dietary administration of L-arginine has been shown to exert anti-atherosclerotic effects in hypercholesterolemic rabbits. Intravenous infusion of L-arginine induces NO-dependent peripheral vasodilatation and inhibits platelet aggregation in healthy humans as well as in patients with severe limb ischemia and generalized atherosclerosis. Whether L-arginine may induce therapeutic effects in peripheral vascular disease, still remains unclear.
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PMID:[Pathogenetic aspects of the L-arginine-NO metabolic pathway in arteriosclerosis and possible therapeutic aspects]. 903 7

We have previously shown that aggregated human platelets elicited a decrease in intracellular adenosine triphosphate (ATP), enhanced adenosine egress and damage to mitochondria in bovine aortic endothelial cells (ECs). To test whether such metabolic and ultrastructural changes could be associated with functional impairment of ECs, we investigated the effects of activated platelets on nitric oxide (NO) and prostacyclin release, and on the antiaggregation property of ECs. Pretreatment of ECs with aggregated platelets transiently stimulated basal NO release while prolonged (> or = 30 min) exposure dose-dependently inhibited NO release, both basal and in response to ATP or serotonin, with NO synthase activity being attenuated in these cells. Supplementary L-arginine (L-A) restored NO release completely. Prostacyclin release was also stimulated transiently but not affected by prolonged pretreatment. The antiaggregation property of ECs was attenuated by pretreatment with activated platelets but restored with L-A supplement. Although the effects of activated platelets and 0.5 mM acetylsalicylic acid (ASA) to attenuate the antiaggregation property of ECs were additive, activated platelets had no effect on ECs treated with 0.2 mM N omega-nitro-L-arginine (L-NA), suggesting a common mechanism. We conclude that prolonged exposure to aggregated platelets may affect the antiaggregation property of ECs by directly inhibiting NO synthesis, which may be normalized by L-A supplementation.
Atherosclerosis 1997 Jan 03
PMID:Impaired NO release from bovine aortic endothelial cells exposed to activated platelets. 905 Nov 94

Nitric oxide (NO) is associated with atherogenic process by inhibiting the proliferation of vascular smooth muscle cells, adhesion of monocyte/macrophages, aggregation and adhesion of platelets and oxidation of LDL, but it is not clear whether NO affects cellular cholesterol metabolism or not. We investigated cholesterol metabolism in murine macrophages (J774A.1) by regulating NO production. Incubation with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, had no influence on cellular cholesterol accumulation induced by LDL or acetylated LDL (acetyl-LDL). Lipopolysaccharide (LPS) stimulated NO production in a dose-dependent manner in the presence of LDL or acetyl-LDL but did not change LDL-induced cellular cholesterol accumulation. In the presence of acetyl-LDL, LPS stimulated NO production but significantly inhibited cholesteryl ester accumulation in a dose-dependent manner (37.7% decrease by 100 micrograms/ml of LPS), but LPS simulation did not change free cholesterol content. NG-monomethyl-L-arginine (L-NMMA), inhibitor of NO synthase, suppressed NO production and addition of L-arginine restored NO production, but these regulations did not alter LPS-induced esterified cholesterol reduction. These results suggest that NO generation in atherosclerotic lesions does not influence cholesterol metabolism in macrophages.
Atherosclerosis 1997 Mar 21
PMID:Effects of nitric oxide on cholesterol metabolism in macrophages. 910 61

A Silastic collar placed around the common carotid artery of rabbits causes the formation, within 7 days, of an atheroma-like neointima containing cells with the appearance of synthetic-phenotype smooth muscle cells. Using immunohisto-chemistry, we detected the appearance of the cytokine-inducible form of nitric oxide synthase (iNOS, or isoform II) in the neointima of rabbits that had the collar in place for 7 or 14 days. This iNOS immunofluorescence collocalized with anti-smooth muscle myosin in the intima, indicating that it is expressed in smooth muscle cells, and iNOS was also present in a few endothelial cells in collared sections. There was no evidence of iNOS expression in the arterial wall before the neointima was apparent, that is, after only 2 days with the collar. The expression of endothelial NOS (eNOS, or isoform III) immunofluorescence was confined to the endothelial cells in control sections, as it was in collared sections with neointima at 7 and 14 days. Specific immunofluorescence for neuronal NOS (nNOS, or isoform I) was not observed in any sections. Our results suggest that nitric oxide is produced by the inducible isoform of NOS in modified smooth muscle cells of the developing neointima. Activity of iNOS might deprive the endothelium of substrate for nitric oxide production and might explain the compromised endothelium-dependent vasodilatation observed both in this model of atherosclerosis and in human coronary artery disease.
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PMID:Induction of nitric oxide synthase in the neointima induced by a periarterial collar in rabbits. 910 88

While estrogen is known to prevent the development of atherosclerosis, the mechanism is not completely understood. We investigated the effects of superoxide dismutase, acetylcholine, and other compounds on the release of nitric oxide (NO) by measuring the relaxation responses of aortic rings, with and without intact endothelium, taken from rabbits under various experimental conditions. The aorta of female rabbits released a greater amount of NO than did that of oophorectomized females and male rabbits. The greater basal release of NO in female rabbits was decreased in animals with atherosclerosis induced by a high cholesterol diet. We also investigated the effect of estrogen on endothelial, neuronal and inducible NO synthase (NOS), NOS-3, NOS-1 and NOS-2, respectively. Preincubation with a physiologic concentration of 17 beta-estradiol (10(-12) to 10(-8) M) over 8 h significantly enhanced the activity of NOS-3 in the endothelial cells of cultured human umbilical vein and bovine aortas. 17 beta-Estradiol also enhanced the release of NO from endothelial cells as measured by an NO selective meter and NO2-/N/3-, metabolites of NO. Western blot showed a similar effect of 17 beta-estradiol on NO. Estrogen increased NOS-3 via a receptor-mediated system. Low concentrations of 17 beta-estradiol (10(-10) to 10(-8) M) enhanced the activity of crude NOS-1 in the cytosolic fraction of rabbit cerebella. Partially purified NOS-1, obtained from the cytosolic fraction by DEAE column chromatography, had a similar response to estrogen. Estrogen at a low dose enhanced the fluorescence of dansyl calmodulin and augmented it in high doses. We also investigated the effect of estrogen on NOS-2. When J774 cells, a murine macrophage cell line, were incubated with interferon-r and lipopolysaccharide, NOS-2 was induced and a large amount of NO was released. Pre- or co-incubation of 17 beta-estradiol inhibited the induction of NOS-2 protein and NO release. The estrogen receptor antagonists, tamoxifen and ICI 182780, inhibited that effect of 17 beta-estradiol. 17 beta-Estradiol inhibited the induction of NOS-2 by a receptor-mediated system. These results may offer a new mechanism for the anti-atherosclerotic effect of 17 beta-estradiol.
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PMID:Effect of estrogen on isoforms of nitric oxide synthase: possible mechanism of anti-atherosclerotic effect of estrogen. 918 36

The endothelium modulates vascular tone by producing vasodilator vasoconstrictor substances. Of these, the most well characterized and potentially important are .NO and .02-. These small molecules exhibit opposing effects on vascular tone, and chemically react with each other in a fashion which negates their individual effects and leads to the production of potentially toxic substances. These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. .NO is produced in endothelial cells by an enzyme termed nitric oxide synthase. The endothelial .NO-synthase is activated when the intracellular level of calcium is increased. This occurs in response to neurohormonal stimuli and in response to shear stress. Acetylcholine and substance P are examples of neurohumoral substances that are able to stimulate the release of nitric oxide and to assess endothelial regulation of vasomotor tone. Importantly, the vasodilator potency of nitric oxide released by the endothelium is abnormal in a variety of diseased states such as hypercholesterolemia, atherosclerosis and diabetes mellitus. This may be secondary to decreased synthesis of nitric oxide or increased degradation of nitric oxide due to superoxide anions. More recent experimental observations demonstrate increased production of superoxide in atherosclerosis, diabetes mellitus and high renin hypertension suggesting that endothelial dysfunction in these states is rather secondary to increased .NO metabolism rather than due to decreased synthesis of .NO. Superoxide rapidly reacts with nitric oxide to form the highly reactive intermediate peroxynitrite (ONOO-). Peroxynitrite can be protonated to form peroxynitrous acid which in turn can yield the hydroxyl radical (OH.). These reactive species can oxidize lipids, damage cell membranes, and oxidize thiol groups. .NO given locally, exerts potent antiatherosclerotic effects such as inhibition of platelet aggregation, inhibition of adhesion of leukocytes and the expression of leukocyte adhesion molecules. It is important to note, however, that in-vivo treatment with .NO (via organic nitrates) increases rather than decreases oxidant load within endothelial cells. It remains therefore questionable whether systemic treatment with .NO may have antiatherosclerotic properties or whether .NO may initiate or even accelerate the atherosclerotic process.
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PMID:The physiology and pathophysiology of the nitric oxide/superoxide system. 923 65

The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis.
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PMID:Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits. 925 81

Inducible nitric oxide synthase (iNOS) is a high-output isoform of NOS that produces nitric oxide (NO), a nonspecific immune effector molecule. In some animal models of autoimmunity, the induction of iNOS has been shown to lead to inflammation and tissue damage, and it has been suggested that iNOS is an immune mediator in humans as well. Using in situ hybridization and immunohistochemical techniques, we demonstrate that iNOS mRNA and protein are present in the coronary arteries of transplanted human hearts with accelerated graft arteriosclerosis (AGA). iNOS is expressed in cells morphologically consistent with macrophages in the neointima of 7 of 10 of the transplanted vessels with AGA that were examined. In serial sections, these same cells express the macrophage marker CD68. In contrast, iNOS is absent from five native coronary arteries with atherosclerosis and absent from two normal coronary arteries. Although iNOS is expressed in macrophages in AGA, its role in the pathogenesis of AGA is unknown.
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PMID:Inducible nitric oxide synthase expression in coronary arteries of transplanted human hearts with accelerated graft arteriosclerosis. 932 24

We evaluated the effects of nipradilol, a beta-adrenoreceptor antagonist which contains a nitroxy residue, for vascular response in atherosclerosis of rabbits. Four groups of rabbits received different diets (standard diet; standard diet plus 10 mg/kg/day nipradilol; atherogenic diet [standard diet plus 1% cholesterol]; atherogenic diet plus 10 mg/kg/day nipradilol) for 9 weeks. Plasma lipids, blood pressure, vascular function, nitric oxide (NO), activity of NO synthase, cGMP, and histological atherosclerotic changes were evaluated. Neither the atherogenic diet nor nipradilol treatment affected significantly the animals' body weight, blood pressure, or heart rate. The atherogenic diet increased total cholesterol and triglycerides, which were not altered by nipradilol. The atherogenic diet diminished the acetylcholine-induced NO mediated relaxation. Nipradilol treatment restored this relaxation. Analyses using a NO-sensitive selective electrode showed that nipradilol released NO in the presence of cells and that NO release was greater in atherosclerotic aorta with than without nipradilol treatment. Nipradilol treatment increased the basal NO release as evaluated by the aortic tissue cyclic GMP (cGMP) levels in atherosclerotic vessel, and reduced the esterified cholesterol levels in atherosclerotic vessel. Conclusively, NO released by nipradilol may protect endothelium derived relaxation in atherosclerotic vessels, and may partially inhibit the accumulation of cholesterol in the atherosclerotic lesions.
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PMID:The beta adrenoreceptor antagonist, nipradilol, preserves the endothelial nitric oxide response in atherosclerotic vessels of rabbit. 933 27


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