UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A critical early event in the pathogenesis of occlusive vascular disease is the adhesion of monocytes to endothelial cells. The authors have previously reported that insulin-like growth factor-1 increases monocyte-endothelial cell adhesion and increases the expression of intercellular adhesion molecule-1. In this study, it is hypothesized that the upregulation of intercellular adhesion molecule-1 expression after treatment with insulin-like growth factor-1 is caused by an increase in the transcription of intercellular adhesion molecule-1 in endothelial cells, and that this transcription is regulated, at least in part, by activation of nuclear factor-kappaB. Adherence cell assays were performed using insulin-like growth factor-1 treated human umbilical vein endothelial cells and human monocytes. To determine the role of nuclear factor-kappaB, Western blotting using the anti-p65 (activated portion of nuclear factor-kappaB) was performed on cell lysate of human umbilical vein endothelial cells treated with insulin-like growth factor-1. RT-PCR was performed on RNA extracted from insulin-like growth factor-1-treated human umbilical vein endothelial cells. Intercellular adhesion molecule-1 antibody attenuated the increase in monocyte-endothelial cell adhesion of endothelial cells exposed to insulin-like growth factor-1. We observed an increase in expression of the activated nuclear factor-kappaB p65 protein in response to insulin-like growth factor-1 treatment. Peak increase occurred at 30 min. This effect was sensitive to pretreatment of human umbilical vein endothelial cells with the insulin-like growth factor-1 receptor antibody. Human umbilical vein endothelial cells treated with insulin-like growth factor-1 for 2 and 4 h revealed a significant increase in intercellular adhesion molecule-1 mRNA as compared with untreated human umbilical vein endothelial cells. Tumor necrosis factor-alpha produced a larger increase in intercellular adhesion molecule-1 mRNA expression. These results suggest that insulin-like growth factor-1 enhances intercellular adhesion molecule-1 transcription and activates nuclear factor-kappaB in endothelial cells. The intracellular pathways that increase cell adhesion molecule expression may provide a common link to understanding the monocyte-endothelial cell adhesion that occurs in the early stages of atherosclerosis and restenosis.
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PMID:Insulin like growth factor-1 activates nuclear factor-kappaB and increases transcription of the intercellular adhesion molecule-1 gene in endothelial cells. 1007 67

We have shown previously that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) induces monocyte but not neutrophil binding. This monocyte binding was not mediated by endothelial E-selectin, P-selectin, vascular cell adhesion molecule-I, or intercellular adhesion molecule-I, suggesting an alternative monocyte-specific adhesion molecule. We now show that moncytic alpha4beta1 integrins mediate binding to MM-LDL-treated endothelial cells. We present data suggesting that the expression of the connecting segment-1 (CS-1) domain of fibronectin (FN) is induced on the apical surface of HAEC by MM-LDL and is the endothelial alpha4beta1 ligand in MM-LDL-treated cells. Although the levels of CS-1 mRNA and protein were not increased, we show that MM-LDL treatment causes deposition of FN on the apical surface by activation of beta1integrins, particularly those associated with alpha5 integrins. Activation of beta1 by antibody 8A2 also induced CS-1-mediated monocyte binding. Confocal microscopy demonstrated the activated beta1 and CS-1colocalize in concentrated filamentous patches on the apical surface of HAEC. Both anti-CS-1 and an antibody to activated beta1 showed increased staining on the luminal endothelium of human coronary lesions with active monocyte entry. These results suggest the importance of these integrin ligand interactions in human atherosclerosis.
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PMID:Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating beta1 integrin. 1007 78

Vascular cell adhesion molecule-1 (VCAM-1) is a mononuclear leukocyte-selective adhesion molecule that is expressed in human vascular endothelial cells at sites of local inflammation. It participates in local endothelial-monocyte interactions during the initiation of atherosclerosis. In the present study, endothelin alone did not induce the surface expression and mRNA accumulation of VCAM-1 in human vascular endothelial cells, but inhibition of endogenous nitric oxide (NO) by N(G)-monomethyl-L-arginine enhanced the surface expression and mRNA accumulation of VCAM-1 stimulated by endothelin-1. It is conceivable that in human vascular endothelial cells, stimulation of an endothelin receptor results in the production of nitric oxide (NO), suppressing the expression of VCAM-1. Endothelin-1 enhanced the surface expression and mRNA accumulation of VCAM-1 in cells treated with tumor necrosis factor alpha (TNF-alpha). The enhancement by endothelin-1 may be explained by the inhibitory effect of TNF-alpha on endothelin-induced NO production. Pretreatment with BQ788 (an endothelin ET(B) receptor antagonist) or inhibitors of nuclear factor kappa B (NF-kappaB) activation completely diminished the synergistic enhancement of VCAM-1 expression by endothelin-1 in TNF-alpha-stimulated vascular endothelial cells, both at the protein and mRNA levels. These findings suggest that the synergistic enhancement of VCAM-1 expression by TNF-alpha and endothelin ET(B) receptor stimulation may be augmented by the induction of NF-kappaB binding activity in human vascular endothelial cells.
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PMID:Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor alpha-stimulated vascular endothelial cells. 1020 85

The measurement of leukocyte rheology in vascular disease is a recent development with a wide range of new opportunities. The International Society of Clinical Hemorheology has asked an expert panel to propose guidelines for the investigation of leukocyte rheology in clinical situations. This article first discusses the mechanical, adhesive and related functional properties of leukocytes (especially neutrophils) which influence their circulation, and establishes the rationale for clinically-related measurements of parameters which describe them. It is concluded that quantitation of leukocyte adhesion molecules, and of their endothelial receptors may assist understanding of leukocyte behaviour in vascular disease, along with measurements of flow resistance of leukocytes, free radical production, degranulation and gene expression. For instance, vascular cell adhesion molecule (VCAM-1) is abnormally present on endothelial cells in atherosclerosis, diabetes mellitus and inflammatory conditions. Soluble forms of intercellular adhesion molecule (ICAM-1) or VCAM can be found elevated in the blood of patients with rheumatoid arthritis or infections disease. In the second part of the article, possible technical approaches are presented and possible avenues for leukocyte rheological investigations are discussed.
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PMID:Measurement of leukocyte rheology in vascular disease: clinical rationale and methodology. International Society of Clinical Hemorheology. 1051 84

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E(-/-) (deficient) mice fed a normal chow diet. All mice were apo E(-/-) and CAM(+/+) or CAM(-/-) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 +/- 0. 65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin null mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.
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PMID:P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. 1062 Jun 17

The adhesion of monocytes to endothelium, an early event in atherosclerosis, is mediated by cell adhesion molecules. Signal-transduction pathways for these binding molecules include the translocation of the transcription factor NF-kappaB; moreover, intracellularly generated oxygen-derived free radicals (ODFR) play a major role in this process. This study evaluated the extent to which troglitazone, an oral antidiabetic agent with antioxidant properties, affects the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells (HUVECs), induced by different prooxidant signals such as oxidized LDL and tumor necrosis factor-alpha (TNF-alpha). Furthermore we assessed whether the NF-kappaB activation is modulated by the antioxidative effect of troglitazone. Oxidized LDL not only caused a dose-dependent increase of ICAM-1, VCAM-1 and E-selectin (p<0.001), but also synergically increased their TNF-alpha-induced expression (p<0.001). Troglitazone reduced in a dose-dependent manner the expression of VCAM-1, ICAM-1 and E-selectin induced by different amounts of oxidized LDL (p<0.001). The addition of troglitazone to HUVECs significantly reduced the expression of ICAM-1, VCAM-1 and E-selectin induced by TNF-alpha alone or in combination with oxidized LDL (p<0.001); this reduction was paralleled by a significant fall in NF-kappaB translocation. The results suggest that troglitazone may have prevented NF-kappaB-mediated adhesion molecule expression by exerting its antioxidant effect on ODFR.
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PMID:The expression of adhesion molecules on endothelial cells is inhibited by troglitazone through its antioxidant activity. 1062 6

Adhesion of leukocytes to endothelial cells via cell adhesion molecules (CAMS) is thought to be pivotal in the initiation of atherosclerosis. As patients with familial hypercholesterolaemia (FH) are known to develop severe, premature coronary artery disease (CAD), we investigated the usefulness of soluble forms of CAMS namely vascular cellular adhesion molecule-1 (VCAM), intercellular cell adhesion molecule-1 (ICAM) and E-selectin as predictive markers of the presence and severity of atherosclerosis in this patient group. Twenty heterozygous FH patients without CAD; 24 heterozygous FH patients with CAD; 17 homozygous FH patients without documented CAD; nine homozygous FH patients with overt CAD; and 50 healthy controls were studied. Carotid artery intima media thickness (IMT) was also measured in the homozygous patients. Levels of the adhesion molecules VCAM, ICAM and E-selectin were not significantly elevated in homozygous FH patients and heterozygous FH patients, both with and without CAD, compared to the normal control subjects. In addition the range of results was so wide and the overlap of values with normal controls so great, that the use of an individual level of either VCAM, ICAM or E-selectin was not predictive of either the presence or degree of atherosclerosis in the FH subjects.
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PMID:Cell adhesion molecules - can they be used to predict coronary artery disease in patients with familial hypercholesterolaemia? 1069 26

The adherence of monocytes to the endothelium is an early event in atherogenesis which is modulated by low density lipoproteins (LDL). We analyzed the effect of atherogenic LDL levels (180 mg cholesterol/dl, for 24 h) with minimal oxidative modifications (thiobarbituric-acid-reactive-substances (TBARS) concentration between 1.2+/-0.1 and 2.5+/-0.3 nmol of malonaldehyde bis-diethyl acetal (MDA) per mg protein) on human umbilical vein endothelial cell (HUVEC) adhesive properties. We used native LDL (n-LDL), and LDL exposed to spontaneous oxidation without antioxidants (mox-LDL) or with 20 micromol/l of the antioxidant butylated hydroxytoluene (BHT-LDL) or 10 micromol/l U74500A (U74500A-LDL), a scavenger of free radicals. Thiobarbituric-acid-reactive-substances (TBARS) levels were significantly higher in mox-LDL (2.5+/-0.3 nmol MDA/mg protein) than in BHT-LDL (1.6+/-0.2), U74500A-LDL (1.2+/-0.1) or in n-LDL (1.3+/-0.1). mox-LDL induced the greatest adhesion of U937 cells to HUVEC (103+/-9% over controls) followed by BHT-LDL (75+/-10%), U74500A-LDL (36+/-9%) and n-LDL (35+/-3%). The lazaroid U74500A efficiently protected U74500A-LDL against oxidative damage and prevented endothelial adhesiveness associated with this LDL modification, inducing adhesion effects similar to those of n-LDL. However, U74500A could not reverse the adhesion induced by previously oxidized LDL (mox-LDL). LDL did not induce the expression of the intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) or E-selectin, but it produced a downregulation of endothelial nitric oxide synthase (NOS III) mRNA levels. Thus, adhesiveness of human endothelial cells (EC) exposed to atherogenic concentrations of LDL is closely modulated by minimal changes in LDL oxidative state, and could be related to a downregulation of NOS III.
Atherosclerosis 2000 Apr
PMID:Small oxidative changes in atherogenic LDL concentrations irreversibly regulate adhesiveness of human endothelial cells: effect of the lazaroid U74500A. 1072 79

Although age is a strong risk factor for atherosclerosis, it is unclear whether age may directly influence the process of atherogenesis. We, therefore, performed several studies in young (2-4 months old), mature (10-14 months old), and old (20-22 months old) mice to determine if the rate of aortic lesion formation increases with age, and whether this is related to increases in oxidative stress or vascular cell adhesion molecule (VCAM-1) expression in the aortic wall. In chow-fed low-density lipoprotein receptor-deficient (LDLR-/-) mice, plasma total cholesterol levels increased with age (250 +/- 52 mg/dl in young, 276 +/- 58 in mature, and 314 +/- 101 mg/dl in old mice). In contrast, the extent of atherosclerosis rose more rapidly, increasing from 3.6 +/- 2.7% of the aortic surface in mature mice to 18.2 +/- 8% in old mice. Plasma and tissue levels of antioxidant enzymes and molecules, as well as plasma thiobarbituric acid reactive substances and low-density lipoprotein susceptibility to oxidation, did not change with age. In a second study, VCAM-1 expression in the aortic arch and the extent of atherosclerosis in the aortic origin were significantly greater in old LDLR-/- mice than in young LDLR-/- mice. Additionally, after 1 month of a high-fat diet, which induced equally elevated plasma cholesterol levels in both young and old LDLR-/- mice, VCAM-1 expression and aortic lesion formation were still greater in old mice. The extent of atherosclerosis correlated well (r = .65,p <.01) with the expression of VCAM-1 in the aortic origin. In a final study, we measured VCAM-1 expression and atherosclerosis in young, mature, and old C57BL/6 mice, which have low plasma cholesterol levels (< or =100 mg/dl) when fed a standard chow diet. Although plasma cholesterol levels did not increase with age, old C57BL/6 mice had significantly more VCAM-1 expression in the aortic arch than did young mice. However, no lesions were observed in the aortic origin in either group. These data demonstrate that plasma cholesterol levels and VCAM-1 expression increase with age and suggest that this may contribute to the increased rate of atherosclerotic lesion formation in LDLR-/- mice. Importantly, the age-dependent increase in VCAM-1 expression does not appear to be related to plasma cholesterol levels. This study also suggests that in the absence of elevated plasma cholesterol, an increased expression of VCAM-1 alone is not sufficient for lesion formation.
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PMID:Effect of aging on aortic expression of the vascular cell adhesion molecule-1 and atherosclerosis in murine models of atherosclerosis. 1073 83

Levels of soluble cellular adhesion molecules are increased in patients with atherosclerosis, and have been found to predict coronary heart disease. Therefore these molecules have been suggested to represent laboratory markers for inflammation and activation of endothelial cells. Impaired endothelium-dependent vasodilation has been demonstrated to be an early marker of atherosclerosis. We hypothesized that soluble adhesion molecules are related to impaired endothelium-dependent vasodilation and may serve as an early marker of atherosclerosis. Patients (n=52) with moderate and uncomplicated hypercholesterolaemia [low-density lipoprotein (LDL)-cholesterol 4.89+/-1.26 mmol/l] were compared with healthy controls (n=43; LDL-cholesterol 2.44+/-0.79 mmol/l). Endothelium-dependent vasodilation of the forearm vasculature was assessed by intra-arterial infusion of acetylcholine (12 and 48 microg/min). Forearm blood flow was measured by venous occlusion plethysmography. Plasma concentrations of the soluble forms of ICAM-1 (intercellular cell adhesion molecule-1), VCAM-1 (vascular cell adhesion molecule-1) and E-selectin were measured by ELISA. Hypercholesterolaemic patients had impaired endothelium-dependent vasodilation in comparison with healthy controls (forearm blood flow after 48 microg/min acetylcholine: 21.3+/-10.6 and 30.4+/-16.3 ml. min(-1).100 ml(-1) respectively; P=0.002). Plasma concentrations of soluble adhesion molecules were not different between hypercholesterolaemic patients and controls (ICAM-1, 196+/-56 and 180+/-38 ng/ml respectively; VCAM-1, 431+/-137 and 405+/-65 ng/ml respectively; E-selectin, 39+/-17 and 37+/-12 ng/ml respectively). Moreover, levels of soluble adhesion molecules were not correlated with endothelium-dependent vasodilation. Thus, in hypercholesterolaemic patients without clinical atherosclerosis, levels of soluble adhesion molecules were not elevated in comparison with healthy controls. In addition, these markers of endothelial inflammation were not related to impaired endothelium-dependent vasodilation. Our data indicate that measurement of levels of soluble adhesion molecules cannot replace assessment of endothelium-dependent vasodilation in detection of early hypercholesterolaemic atherosclerosis.
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PMID:Plasma soluble adhesion molecules and endothelium-dependent vasodilation in early human atherosclerosis. 1078 82

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