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)

Recent evidence indicates that chronic hyperhomocysteinemia, which is found in from 9 to 15% of the general population, is an independent risk factor for the development of atherosclerosis. We sought to elucidate the mechanism by which exposure of the vascular wall to high levels of homocysteine initiates this inflammatory reaction. We examined the acute effect of homocysteine on endothelial dysfunction in isolated rat arteries and on microcirculatory leukocyte-endothelium interaction in vivo. Intravital microscopy of rat mesenteric venules was performed by superfusing the mesentery with increasing concentrations of homocysteine (1-5 mmol/l). There was a significant concentration- and time-dependent increase in leukocyte rolling, adherence, and extravasation compared with control rats superfused with Krebs-Henseleit solution (p < 0.01). Moreover, immunohistochemical staining demonstrated significantly increased P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression on intestinal venules after homocysteine superfusion. In contrast, mesenteric superfusion with the nitric oxide donor 4-hydroxymethyl-furazan-3-carboxylic acid oxide (CAS1609, 1 micromol/l) significantly attenuated homocysteine-induced leukocyte rolling, adherence, and transmigration to control levels (p < 0.01). CAS1609 also attenuated both P-selectin and ICAM-1 expression on mesenteric venules and decreased CD18 expression on isolated leukocytes. Superior mesenteric arteries incubated with 5 mmol/l homocysteine developed significant (p < 0.01) endothelial dysfunction (i.e., impaired relaxation to endothelium-dependent dilators). Acute hyperhomocysteinemia induces endothelial dysfunction, characterized by a loss of endothelium-derived nitric oxide, leading to an inflammatory state. This state results in increased leukocyte rolling, adherence, and transmigration by upregulation of cell adhesion molecules. Our data suggest that hyperhomocysteinemia inhibits the important homeostatic role of nitric oxide in preventing endothelial dysfunction.
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PMID:Homocysteine provokes leukocyte-endothelium interaction by downregulation of nitric oxide. 1064 74

Positivity for circulating intercellular adhesion molecule-1 (ICAM-1) in heart transplant recipients has been claimed to predict the development of coronary artery disease and risk of graft failure. Soluble ICAM-1 were evaluated in 32 heart transplant recipients. Five of these patients, who had undergone transplantation several years before, were positive for soluble ICAM-1 but did not present any clinical sign of graft rejection. Furthermore, although heart graft coronary disease was diagnosed in 15 of the 32 patients, they did not show significantly higher titres of soluble ICAM-1 compared to the remaining patients. These findings suggest that major caution is necessary when considering ICAM-1 positivity as a marker of graft disease.
Atherosclerosis 2000 Feb
PMID:Are elevated levels of soluble ICAM-1 a marker of chronic graft disease in heart transplant recipients? 1065 64

Fas ligand (FasL) is expressed by cells of the arterial wall and is present in human atherosclerotic lesions. However, the role of FasL in modifying the initiation and progression of atherosclerosis is unclear. To investigate the role of arterial FasL expression in the development of atherosclerosis, we first established a model of primary lesion formation in rabbit carotid arteries. In this model, infusion of adenoviral vectors into surgically isolated, nondenuded arteries of hypercholesterolemic rabbits leads to the formation of human-like early atherosclerotic lesions. Expression of FasL in arterial endothelium in this model decreased T-cell infiltration and expression of vascular cell adhesion molecule-1 but did not affect expression of intercellular adhesion molecule-1. Intimal lesions grew more rapidly in FasL-transduced arteries than in arteries transduced with a control adenovirus that did not express a transgene. Total intimal macrophage accumulation was increased in FasL-transduced arteries; however, the proportion of lesion area occupied by macrophages was not elevated. The accelerated lesion growth was primarily due to the accumulation of intimal smooth muscle cells with a synthetic proliferative phenotype. There was no significant apoptosis in FasL-transduced or control arteries and no granulocytic infiltrates. Thus, the net result of elevated FasL expression is to accelerate atherosclerotic lesion growth by increasing lesion cellularity. Vascular expression of FasL may contribute to the progression of atherosclerosis.
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PMID:Expression of Fas ligand in arteries of hypercholesterolemic rabbits accelerates atherosclerotic lesion formation. 1066 24

Damage to the endothelium is an important component of atherosclerosis and can be quantified by measuring plasma markers, such as von Willebrand factor, thrombomodulin, intercellular adhesion molecule-1, and E-selectin. We hypothesized that increased levels of these markers would be related to objectively defined disease severity among patients with peripheral atherosclerosis or carotid atherosclerosis. To test this, we measured the markers by using ELISA in the plasma of 45 patients with intermittent claudication alone and in 53 patients presenting with transient ischemic attack. Disease severity in the former was by ankle-brachial pressure index and in the latter by ultrasound defined % stenosis. Any symptomatic dual disease or history or present coronary atherosclerosis warranted exclusion. Data were correlated according to Spearman's method. The only significant correlation was between von Willebrand factor and ankle-brachial pressure index (r = -0.39, p = 0.008). Our data suggest that von Willebrand factor is the most sensitive marker of peripheral atherosclerosis and that none of the plasma markers seems to be a useful marker of the degree of carotid artery stenosis.
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PMID:Relationship between endothelial cell markers and arterial stenosis in peripheral and carotid artery disease. 1067 7

Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with type 2 diabetes mellitus (n = 64) and control subjects (n = 40) were studied. Serum ICAM-1 concentrations in diabetic patients were significantly higher than those of control subjects (378.2 +/- 70.0 versus 220.4 +/- 31.8 ng/ml, P < 0.01). By multiple regression analysis, hemoglobin A1c was independently associated with serum ICAM-1 concentration in patients with diabetes. The serum VCAM-1 concentration of diabetic patients with macroangiopathy was higher than those of patients without macroangiopathy and of control subjects (806.9 + 276.5 versus 639.0 +/- 146.0 (P < 0.01), and 652.1 +/- 146.9 ng/ml (P < 0.01), respectively). There was no difference in serum E-selectin concentration between diabetic patients with or without macroangiopathy and normal control subjects. These results suggest that adhesion molecules may contribute to the development of atherosclerosis in the diabetic state.
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PMID:Circulating intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in patients with type 2 diabetes mellitus. 1072 93

Endothelial cell injury has been implicated in the increased incidence of vascular disease associated with diabetes mellitus. In diabetic humans, elevated plasma von Willebrand Factor (vWF) has been interpreted as an indication of endothelial damage. In contrast, in an animal model of inherited insulin-dependent diabetes, the bio-breeding (BB) rat, plasma vWF levels did not differ from those in age-matched control rats during the first 7 months of diabetes although morphological evidence of mild aortic endothelial alteration or injury was observed. In the present study efforts have been made to define the endothelial alterations in BB diabetic rats compared to controls more precisely over this time period. Thus, adhesion molecules: intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1(VCAM-1) were evaluated by in situ immunohistochemistry, vWF content was determined by biochemical analysis of aortic extracts and by quantitative immunohistochemistry, plasma vWF levels were measured by ELISA and vWF mRNA by RNAse protection assay. Neither age nor diabetic state significantly affected either the expression of adhesion molecules, or the levels of circulating vWF. Endothelial vWF content was significantly increased in the diabetic vessels, as observed by both approaches but the vWF mRNA content was not different from that in control vessels. Plasma plasminogen activator inhibitor (PAI-1) activity was significantly increased in diabetic animals. In conclusion, endothelial alterations in BB rats associated with diabetes, together with the raised plasma PAI-1 levels, promote the thrombogenic potential of the vessel wall, and are consistent with an increased risk for vascular disease.
Atherosclerosis 2000 Apr
PMID:Aortic endothelial cell von Willebrand factor content, and circulating plasminogen activator inhibitor-1 are increased, but expression of endothelial leukocyte adhesion molecules is unchanged in insulin-dependent diabetic BB rats. 1072 83

The mechanism behind the development of vascular complications of hypertension in the young human remains unclear. To explore the role of vascular endothelium-generated nitric oxide (a known mediator of leucocyte-platelet-endothelial interactions) in this context, we investigated markers of endothelial activation (soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin), and von Willebrand factor and the plasma level of the endogenous nitric oxide inhibitor asymmetric dimethyl arginine (ADMA) in a group of 31 (17 male, mean age 9.4 years) hypertensive and 9 (4 male, mean age 9.1 years) healthy, normotensive children and young adults. We found raised levels of ADMA (mean (SEM) 235 (32) n mol/l) and VCAM-1 (median (range) 1237 (675-2700) ng/ml) in the plasma of hypertensive subjects compared with those of normotensives (ADMA, 103 (7) n mol/l and VCAM-1, 1005 (425-1650) ng/ml, respectively). Furthermore, in hypertensive subjects, higher VCAM-1 concentrations (r = 0.66, p < 0.001) and vWF concentrations (r = 0.37, p = 0.04) were significantly associated with a higher plasma ADMA level. Therefore, an isolated increase in plasma VCAM-1 in hypertensives in association with raised ADMA may signify a selective "non-inflammatory" endothelial activation triggered by endothelial nitric oxide synthase inhibition. Since VCAM-1 is implicated in the origins of atherosclerosis, ADMA may be an important contributory factor in increasing the risk of atheroma formation in hypertensive children and young adults.
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PMID:Vascular endothelial cell activation associated with increased plasma asymmetric dimethyl arginine in children and young adults with hypertension: a basis for atheroma? 1085 1

The transcriptional regulatory protein nuclear factor kappa B (NF-kappa B) participates in the control of gene expression of many modulators of inflammatory and immune responses, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). The heightened expression of these adhesion molecules has been reported to play a critical role in atherosclerosis, inflammation, ischemic vascular disorders, diabetes, and cancer metastasis. In the present study, we investigated the effect of pycnogenol, an antioxidant phytochemical, on the activation of NF-kappa B and the induction of VCAM-1 and ICAM-1 in tumor necrosis factor (TNF)-alpha-treated human umbilical vein endothelial cells (HUVECs). Gel-shift analysis of HUVEC demonstrated that pretreatment with pycnogenol exhibited a concentration-dependent suppression of TNF-alpha-induced activation of NF-kappa B. Induction of VCAM-1 and ICAM-1 surface expression by TNF-alpha was dose-dependently reduced by pycnogenol. TNF-alpha significantly increased the release of superoxide anion and hydrogen peroxide from HUVECs. Pycnogenol dose-dependently inhibited their release. The ability of pycnogenol to inhibit NF-kappa B activation and VCAM-1 and ICAM-1 expression suggests that this phytochemical may play an important role in halting or preventing the atherogenic process.
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PMID:Pycnogenol inhibits tumor necrosis factor-alpha-induced nuclear factor kappa B activation and adhesion molecule expression in human vascular endothelial cells. 1089 47

Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidonic acid products, such as prostaglandin (PG) H(2), PGF(2alpha), hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA(2) in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg. kg(-1). d(-1)) or S18886 (5 mg. kg(-1). d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabolite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB(2) levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA(2). S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA(2) synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA(2), perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).
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PMID:The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. 1089 3

It has been shown that endothelial cell adhesion molecules play an important role in the development of coronary atherosclerosis and inflammatory disease. We sought to test whether soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin are increased in patients with documented coronary artery disease (CAD). Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured in 40 patients with documented CAD, 20 subjects with angiographically documented normal coronary arteries, and 14 healthy volunteers. Patients with documented CAD exhibited significant elevation of VCAM-1 (535 +/- 227.1 ng/ml, p = 0.0001), E-selectin (69.4 +/- 29.4 ng/ml, p = 0.006), but not ICAM-1 (320.5 +/- 65.1 ng/ml, p = 0.9) concentrations as compared to subjects with normal coronary arteries (252.3 +/- 79.8, 49.7 +/- 22.0 and 311.4 +/- 40.2 ng/ml), and healthy controls (110.0 +/- 17.7, 29.0 +/- 2.0 and 237.5 +/- 46.5 ng/ml), respectively. Soluble markers of endothelial injury are not uniformly increased in patients with documented CAD as compared to those with normal coronary arteries and healthy controls. However, VCAM-1 and E-selectin, but not ICAM-1 could identify endothelial injury in such patients.
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PMID:Soluble VCAM-1 and E-selectin, but not ICAM-1 discriminate endothelial injury in patients with documented coronary artery disease. 1089


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