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)

Nitric oxide reacts with superoxide to form peroxynitrite, a potential mediator of oxidant-induced cellular injury. The endothelium is a primary target of injury in many pathological states, including acute lung injury, sepsis, multiple organ failure syndrome, and atherosclerosis, where enhanced production of nitric oxide and superoxide occurs simultaneously. It was hypothesized that stimulation of endothelial cell nitric oxide production would result in formation of peroxynitrite. Immediate oxidant production was detected by luminol- and lucigenin-enhanced chemiluminescence from cultured bovine aortic endothelial cells exposed to bradykinin or to the calcium ionophore A23187. Luminol-enhanced chemiluminescence was efficiently inhibited by the nitric oxide synthase inhibitor nitro-L-arginine methyl ester and by superoxide dismutase, implying dependence on the presence of both nitric oxide and superoxide for oxidant production. Inhibition of luminol-enhanced chemiluminescence by nitro-L-arginine methyl ester was partially reversed by L-arginine, but not by D-arginine. Cysteine, methionine, and urate, known inhibitors of peroxynitrite-mediated oxidation, inhibited luminol-enhanced chemiluminescence, while the hydroxyl radical scavengers, mannitol and dimethylsulfoxide, and catalase did not. Bicarbonate increased luminol-enhanced chemiluminescence in a concentration-dependent manner. Superoxide production, detected by lucigenin-enhanced chemiluminescence, was slightly increased in the presence of nitro-L-arginine methyl ester, suggesting that endothelial cell-produced superoxide was partially metabolized by reaction with nitric oxide. These results are consistent with agonist-induced peroxynitrite production by endothelial cells and suggests that peroxynitrite may have an important role in oxidant-induced endothelial injury.
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PMID:Agonist-induced peroxynitrite production from endothelial cells. 817 19

An enhanced risk for myocardial infarction has been observed in humans with sustained activation of the local and/or systemic renin-angiotensin system, such as a high renin-sodium profile or a heritably enhanced expression of angiotensin converting enzyme. Chronic renin-angiotensin system blockade by angiotensin converting enzyme inhibition reduces the rate of myocardial reinfarction in patients with moderate heart failure. Preliminary experimental evidence suggests that these clinical observations may be partially explained by a proatherogenic effect of an activated renin-angiotensin system, which can downregulate the expression of the endothelial nitric oxide synthase III. Nitric oxide exerts many potentially antiatherogenic effects on endothelium, platelets and low density lipoproteins and indirectly on monocytes and leukocytes Hypertension-induced chronic distension of elastic arteries upregulates the local renin-angiotensin system in these arteries and thereby downregulates nitric oxide synthase. Enhanced local synthesis of the trophic factor angiotensin-II and reduced releasability of the antitrophic factor nitric oxide appear to cooperate in the trophic adaptation of the distended vessel wall to the enhanced load, but with the disadvantage of enhanced susceptibility for atheroma development due to reduced availability of nitric oxide. Chronic blockade of the renin-angiotensin system by angiotensin converting enzyme inhibitors or by angiotensin receptor type-1 antagonists normalizes a reduced endothelial nitric oxide availability in several models, partially by a bradykinin-dependent mechanism. This endothelial protection proved to attenuate the progression of atherosclerosis in experimental models. The antiatherogenic potential of renin-angiotensin system blockade in humans is presently under study.
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PMID:The endothelium and the renin-angiotensin system. 818 13

Murine peritoneal macrophages treated with gamma-interferon and lipopolysaccharide (activated cells) oxidized low-density lipoprotein (LDL) less readily than unstimulated cells. Activated cells expressed the enzyme nitric oxide synthase, whose activity was measured by the accumulation of nitrite in the culture supernatant. Treatment of activated macrophages with the arginine analogue NG-monomethyl-arginine (NMMA) inhibited nitric oxide synthesis and restored the ability of the cells to oxidize LDL. This treatment had no effect on the ability of unstimulated cells to oxidize LDL. Similarly, LDL oxidation by activated macrophages in arginine-free Ham's F-10 medium was identical to that of unstimulated cells, whereas restoration of arginine to the medium was associated with nitrite secretion and a decline in LDL oxidation by activated cells only. An inverse relationship between nitric oxide synthesis and LDL oxidation was also demonstrated in the presence of diphenylene iodonium, a flavin analogue which is a potent inhibitor of nitric oxide synthase. Thus nitric oxide synthesis appears to mediate the suppression of LDL oxidation which is associated with the activation of mouse macrophages by gamma-interferon and lipopolysaccharide.
Atherosclerosis 1993 Jul
PMID:Autoinhibition of murine macrophage-mediated oxidation of low-density lipoprotein by nitric oxide synthesis. 837 59

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production. 838 23

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. NO is also produced by vascular smooth muscle (VSMC) where it can inhibit proliferation. Since cytokine-activated VSMC proliferation is a major event in the development of atherosclerosis, we investigated the influence of cholesterol (CE)-enrichment of VSMC on cytokine-induced NO synthesis. Treatment of VSMC with native LDL for one week did not promote CE-accretion or alter NO production following exposure to endotoxin (LPS). In contrast, CE-enrichment by cationized LDL augmented LPS-induction of NO synthesis 2-5-fold. While TNF-alpha promoted little NO synthesis in control VSMC, it was very potent after CE-enrichment. Similarly, CE-enrichment augmented IL-1 alpha-induced NO synthesis. However, CE-enrichment did not affect the synergistic induction of NO synthesis by cytokines in combination with IFN-gamma. Our findings suggest that CE-enrichment of VSMC upregulates signal transduction pathways which mediate cytokine and LPS induction of NO synthase activity.
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PMID:Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine-induced nitric oxide synthesis. 844 15

There is increasing evidence that endothelium-derived nitric oxide production is an important mechanism contributing to the regulation of myocardial perfusion during ischemia distal to a coronary stenosis. Studies in conscious chronically instrumented animals have extended observations in isolated arterioles to demonstrate that inhibiting nitric oxide synthase with L-arginine analogs increases the vulnerability of the myocardium to ischemia. The variable extent to which endothelium-dependent function is impaired in human atherosclerosis raises the possibility that abnormalities in resistance vessel control contribute to the functional significance of a fixed epicardial coronary stenosis. This may explain the wide variability between the physiological effects of a given coronary stenosis and its angiographic severity. Aggressive intervention to normalize endothelium-dependent vasodilation and local nitric oxide release may have beneficial effects on the functional significance of a coronary stenosis.
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PMID:Modulation of coronary autoregulatory responses by endothelium-derived nitric oxide. 853 43

Inflammatory cytokines associated with atherosclerosis may be capable of stimulating the synthesis and activity of inducible nitric oxide synthase (iNOS), which could further influence the pathologic features associated with the disease. Although there is a certain amount of indirect evidence to support the presence of iNOS in atherosclerosis, there has been no definitive study to confirm this. This study has assessed the localization of iNOS within human normal and atherosclerotic vessels by immunocytochemistry, Western blotting, and in situ hybridization. Further, activity of NO synthase has been assessed by detection of nitrotyrosine, which is a marker indicative of the formation and activity of the nitric oxide-derived oxidant, peroxynitrite. In Western blots of crude homogenates of atherosclerotic aorta, the iNOS antiserum reacted with a band of approximately 130 kd (the known molecular weight for iNOS), but no such band was seen in normal aorta. Immunostaining and in situ hybridization confirmed the presence of iNOS in atherosclerotic vessels, in which it was specifically localized to (CD68-positive) macrophages, foam cells, and the vascular smooth muscle. The antiserum to nitrotyrosine reacted with a wide range of protein bands (approximately 180 to 30 kd) in Western blots of atherosclerotic aorta. The distribution of immunostaining for nitrotyrosine was virtually identical to that seen for iNOS and was present in macrophages, foam cells, and the vascular smooth muscle. In conclusion, these studies have demonstrated that stimulated expression of iNOS is associated with atherosclerosis and that the activity of this enzyme under such conditions preferentially promotes the formation and activity of peroxynitrite. This may be important in the pathology of atherosclerosis, which contributes to lipid peroxidation and to vascular damage.
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PMID:Inducible nitric oxide synthase is present within human atherosclerotic lesions and promotes the formation and activity of peroxynitrite. 868 42

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.
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PMID:Preglomerular sudanophilia in L-NAME hypertensive rats: involvement of endothelin. 869 42

The cytokines are multipotent mediators of inflammation and immunity that can affect key functions of vascular wall cells. Growing evidence suggests that cytokines participate as autocrine or paracrine mediators in atherogenesis, as cells in lesions can both produce and respond to these mediators. The functions of vascular wall cells regulated by cytokines may influence lesion initiation, progression, or complication. For example, cytokines can regulate the expression of adhesion molecules crucial to the recruitment of leukocytes to lesions, including vascular cell adhesion molecule-1 (VCAM-1). Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can regulate the production of monocyte chemoattractant protein-1 (MCP-1), a potential signal for directed migration of monocytes into the intima. Cytokines can also regulate genes that encode other growth factors and cytokines themselves. TNF-alpha can induce IL-1 mRNA in human endothelial (EC) and smooth-muscle cells (SMC). IL-1 and TNF-alpha can augment the production by vascular cells of macrophage-colony stimulating factor (M-CSF), which may promote growth and activation of mononuclear phagocytes. Cytokines can exert both pro-and antiatherogenic actions. Activated T cells in human atheroma may secrete the lymphokine IFN-gamma, an inhibitor of SMC proliferation. Cytokines influence vasomotor tone in arteries, e.g., by inducing a form of nitric oxide synthase, the enzyme that synthesizes the vasodilatory nitric oxide radical. The cytokines also modulate endothelial functions that govern the formation and stability of blood thrombi. Finally, in the late stages of the disease, matrix metalloproteinases derived from macrophages or smooth-muscle cells themselves may contribute to weakening of the fibrous cap in the vulnerable shoulder area, promoting plaque rupture and occlusive thrombosis, culminating in the dramatic clinical manifestations of atherosclerosis, including myocardial infarction and stroke. Thus, cytokines can influence multiple aspects of atherogenesis and provide new and interesting targets for therapeutic intervention.
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PMID:Cytokines regulate vascular functions related to stability of the atherosclerotic plaque. 869 71

This article focuses on the key concept that a basal production of nitric oxide (NO) is required as a background for biological modulation, although an excess can be cytotoxic. Studies of ischaemia and neurodegeneration have tended to emphasise detrimental effects of excess NO, but this review contrasts the emerging importance of diminished NO or interference with its action in vasospasm following subarachnoid haemorrhage (SAH) in ageing and in atherosclerosis. Clinical intervention in cerebral ischaemia will require specificity of action, since NO appears to be protective or detrimental depending on the time, source, and distribution of its production. It may be possible to utilise targeted action on the different forms of NO synthase or the specific redox forms of NO in different tissue areas.
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PMID:Nitric oxide and cerebral blood flow: an update. 870 73


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