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

Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. Regulation of VCAM-1 gene expression may be coupled to oxidative stress through specific reduction-oxidation (redox) sensitive transcriptional or posttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1 beta (IL-1 beta) activated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibited the induction of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1), mRNA and protein accumulation by the cytokine tumor necrosis factor-alpha (TNF alpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNF alpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNF alpha but not to LPS, IL-1 beta, or PIC. TNF alpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappa B-like DNA enhancer elements and associated NF-kappa B-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-1 gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis.
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PMID:Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. 769 89

Infiltration of mononuclear cells is an early pathological finding in human and experimental atherosclerosis. However, the cellular and molecular basis for cell infiltration is incompletely understood. While the intercellular adhesion molecule-1 (ICAM-1) is expressed on endothelial cells and promotes the adhesion of mononuclear cells, there is little information on the expression of ICAM-1 on vascular smooth muscle cells (SMC). In this study, we investigated the expression of ICAM-1 on cultured rat SMC and its regulation by pro-inflammatory cytokines, interleukin 1 alpha (IL-1 alpha), interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1). In immunohistochemical staining, ICAM-1 molecules were constitutively expressed on the surface of SMC. In flow cytometric and ELISA analyses, ICAM-1 molecule expression on SMC was significantly upregulated by IL-1 alpha and MCP-1, but not by IL-6, in a dose-dependent manner. The effects of IL-1 alpha and MCP-1 were observed as early as 4 h. In Northern blot analysis, ICAM-1 mRNA was slightly detectable in unstimulated SMC, but its expression was clearly observed following exposure to IL-1 alpha or MCP-1. These results suggest that ICAM-1 on SMC, as well as on endothelial cells, could participate in the focal accumulation of mononuclear cells in human atherosclerotic lesions.
Atherosclerosis 1993 Dec
PMID:Expression of intercellular adhesion molecule-1 on rat vascular smooth muscle cells by pro-inflammatory cytokines. 790 95

The intercellular adhesion of circulating leukocytes to vascular endothelium is a prerequisite for leukocyte emigration from the blood to extravascular tissues. This process is facilitated by adhesion molecules on the surfaces of both the vascular endothelial cells and the leukocytes. The experiments presented here demonstrate for the first time that the leukocyte adhesion receptor, intercellular adhesion molecule-1, is constitutively expressed on cultured cerebromicrovascular endothelial cell lines derived from both spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats. Both cultures contained similar numbers of cells constitutively expressing this adhesion molecule (31.4% and 29.6%, respectively). Adhesion molecule expression was up-regulated by interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma and lipopolysaccharide in a dose- and time-dependent manner. Both cultures exhibited similar maximum levels of adhesion molecule up-regulation to optimal concentrations of all three cytokines. However, SHR endothelial cells were more sensitive to all three cytokines; significantly higher levels of intercellular adhesion molecule-1 expression were seen on SHR as opposed to WKY endothelial cells cultured with sub-optimal cytokine concentrations. It was also observed that lipopolysaccharide up-regulated intercellular adhesion molecule-1 expression on SHR endothelial cells to a greater extent than on WKY endothelial cells. The findings that intercellular adhesion molecule-1 can be up-regulated to a greater degree on SHR endothelial cells may have important implications for in vivo perivascular leukocyte accumulation under hypertensive conditions. These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis and stroke.
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PMID:Adhesion molecules on normotensive and hypertensive rat brain endothelial cells. 790 12

One of the earliest events in atherosclerosis is interaction of circulating mononuclear leukocytes and the endothelium. Endothelial cell (EC) activation by cytokines results in expression of adhesion molecules and production of chemotactic factors, augmenting leukocyte adhesion and recruitment, respectively. The incidence of atherosclerosis in premenopausal women is significantly less than that observed in age-matched males with similar risk profiles. Because estrogen has gene regulatory effects, we investigated whether 17beta-estradiol (E2) can inhibit cytokine-mediated EC adhesion molecule transcriptional activation. Cultured human umbilical vein EC (estrogen receptor-positive) were propagated in gonadal hormone-free medium and were E2-pretreated for 48 h before IL-1 activation. Detected by FACS analysis, E2 strongly (60-80%) inhibited IL-1-mediated membrane E-selectin and vascular cell adhesion molecule-1 induction, and intercellular adhesion molecule-1 hyperinduction. 17alpha-estradiol (an inactive E2 stereoisomer) had no effect. This inhibition correlated with similar reductions in steady state-induced E-selectin mRNA levels, and was abrogated by the E2 antagonist ICI 164,384, demonstrating a specific, estrogen receptor-mediated effect. Nuclear run-offs confirmed suppression at the transcriptional level. The implications of these results for the cardiovascular protective role of estrogen are discussed.
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PMID:Effects of 17beta-estradiol on cytokine-induced endothelial cell adhesion molecule expression. 869 Aug 1

Angiotensin II (AII) is recognized as being an important factor in the pathogenesis of hypertension and atherosclerosis. Monocyte binding to affected endothelial cells is one of the earliest features of atherosclerosis. However, the effect of AII on monocyte binding has not been fully studied. Treatment of human aortic endothelial cells (HAEC) and rabbit aortic endothelial cells (RAEC) for 18 hours with AII induced the adhesion of monocytes but not neutrophils to these cells. This induction was reduced by inhibitors of AII receptors (Type I and Type II). Angiotensin II-induced monocyte binding was not associated with induction of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), or intercellular adhesion molecule-1 (ICAM-1). These results suggest that AII can accelerate the rate of atherosclerosis by increasing monocyte binding to the endothelium.
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PMID:Angiotensin II increases monocyte binding to endothelial cells. 883 2

In addition to preserving hemostasis, fibrinogen assembly on leukocytes mediates inflammatory responses and may aberrantly contribute to vascular injury. In this study, we used real-time intravital video microscopy in exposed rabbit mesentery to investigate the potential role of fibrinogen on leukocyte adherence mechanisms, in vivo. At physiologic concentrations of 0.15 to 0.5 mg/mL, human fibrinogen dose-dependently enhanced by threefold to fivefold the adhesion of chemoattractant-stimulated monocytic HL-60 cells to rabbit mesenteric endothelium, by acting as a bridging molecule between the two types. Fibrinogen-dependent intercellular bridging occurred in venules, but not in arterioles or capillaries (1), was optimal at reduced flow shear forces (range: 0.77 to 2.79 dyne/cm2) (2), and produced a firm attachment of monocytic cells to endothelium, rather than transient rolling (3). Consistent with this model, rabbit fibrinogen failed to support human leukocyte adhesion, while human fibrinogen enhanced monocytic cell attachment to rabbit endothelial cells in vitro, in a reaction indistinguishable from that observed with human endothelium. Antagonists of the recently described association of fibrinogen with intercellular adhesion molecule-1 (ICAM-1), including monoclonal antibodies (MoAbs) LB-2 or 2D5, or the fibrinogen gamma 3 peptide gamma Asn117-Ala133, blocked fibrinogen-dependent leukocyte-endothelium interaction in vitro or in vivo, respectively, while a control nonbinding antibody or the fibrinogen L10 peptide gamma Leu402-Val411 were ineffective. These data suggest that simultaneous assembly of fibrinogen on leukocytes and endothelial ICAM-1 provides a pathway of intercellular adhesion which may act in concert with beta 2 integrins to stabilize firm leukocyte attachment to endothelium, in vivo. Given the recognized role of fibrinogen as a major risk factor for atherosclerosis, this mechanism may directly contribute to thrombus formation and endothelial cell damage in vascular diseases.
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PMID:Fibrinogen mediates leukocyte-endothelium bridging in vivo at low shear forces. 889 6

Leukocyte adhesion to vascular endothelium is a crucial step in the early stages of atherosclerosis, which may be mediated by the interaction of adhesion molecules expressed on the surfaces of both cell types. In this study, we investigated the effects of nitric oxide (NO) on the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). ICAM-1 and VCAM-1 protein and mRNA expression were determined by cellular ELISA and Northern blot analysis, respectively. Both ICAM-1 and VCAM-1 expression were increased markedly by interleukin-1 beta (IL-1 beta). This IL-1 beta-mediated induction of ICAM-1 and VCAM-1 expression was significantly inhibited in the presence of a NO donor 3-morpholino-sydnonimine (SIN-1) in a dose-dependent manner. The inhibitory effect of SIN-1 was abolished in the presence of a NO scavenger haemoglobin, while addition of 8-bromo-cGMP showed no significant effect on IL-1 beta-induced ICAM-1 or VCAM-1 expression. Northern blot analysis showed that IL-1 beta markedly increased ICAM-1 and VCAM-1 mRNA expression, while SIN-1 decreased the accumulation of these transcripts induced by IL-1 beta. These results suggest that NO could prevent the focal adhesion and accumulation of leukocytes through the inhibition of ICAM-1 and VCAM-1 expression in endothelial cells.
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PMID:Nitric oxide attenuates adhesion molecule expression in human endothelial cells. 904 77

Oxidized low-density lipoproteins (oxLDL) have been implicated in the leukocyte recruitment and microvascular dysfunction associated with atherosclerosis. The objectives of this study were to define the adhesion molecules that mediate oxLDL-induced leukocyte-endothelial cell adhesion and to determine whether leukocyte-endothelial cell adhesion contributes to the endothelial barrier dysfunction elicited by oxLDL. Leukocyte-endothelial cell adhesion and emigration, albumin extravasation, and mast cell degranulation were monitored in rat mesentery in response to native LDL (nLDL) or copper-oxidized LDL (oxLDL). Intra-arterial infusion of oxLDL but not nLDL elicited increases in leukocyte adherence and emigration, mast cell degranulation, and albumin leakage. The oxLDL-induced leukocyte adherence/emigration was attenuated by pretreatment with monoclonal antibodies directed against CD11/CD18, intercellular adhesion molecule-1, P-selectin, and L-selectin but not by pretreatment with a nonbinding monoclonal antibody. The albumin leakage and mast cell degranulation responses were attenuated by all of the same monoclonal antibodies except L-selectin. In addition, a peptide previously shown to inhibit leukocyte-endothelial cell adhesion in vitro also attenuated leukocyte adherence and mast cell degranulation in this model. These findings implicate CD11/ CD18, L-selectin, intercellular adhesion molecule-1, and P-selectin in the leukocyte recruitment elicited by oxLDL and invoke a role for adherent leukocytes in the accompanying increase in mast cell degranulation and albumin leakage.
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PMID:Molecular determinants of oxidized low-density lipoprotein-induced leukocyte adhesion and microvascular dysfunction. 910 61

Secondary prevention of atherosclerosis, especially before the onset of symptoms, appears desirable and could be possible with a serum marker detecting atherosclerosis. Circulating, shedded forms of adhesion molecules may serve as such because their expression is upregulated in atherosclerotic plaques. In 52 patients with peripheral arterial vascular disease (Fontaine class IIa, 7 patients; class IIb, 29 patients; and class III, 16 patients), the extent of atherosclerosis was evaluated on the basis of angiograms of a large portion of the arterial system. The area diseased by atherosclerosis was determined by the percentage of vessel wall irregularities of the following calculated segments: aorta (distal from the kidney arteries), common iliac artery, external iliac artery, common femoral artery, lateral circumflex femoral artery, and popliteal artery. The maximal surface area that could exhibit atherosclerotic changes was 250 cm2. The serum concentration of circulating vascular cell adhesion molecule-1 (VCAM-1) correlated with the extent of atherosclerosis (r = .8, P < .001). In contrast, circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin (as markers for endothelial cell damage) did not correlate with the extent of atherosclerosis. Furthermore, circulating VCAM-1 could be used to indicate stages of atherosclerosis with a high degree of statistical significance. The potential bias of factors such as age, diabetes mellitus, hypercholesterolemia, arterial hypertension, renal failure, and history of myocardial infarction on the correlation of circulating VCAM-1 with the extent of atherosclerosis could be excluded by multivariate analysis. These findings suggest an important role of VCAM-1 in atherosclerosis and may serve as the basis for further evaluation of circulating VCAM-1 as a potential serum marker for atherosclerosis.
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PMID:Circulating vascular cell adhesion molecule-1 correlates with the extent of human atherosclerosis in contrast to circulating intercellular adhesion molecule-1, E-selectin, P-selectin, and thrombomodulin. 910 69

It is known that the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the surface of vascular endothelial cells is closely related to the formation of early atherosclerotic lesions. In this study, serum soluble ICAM-1(sICAM-1) and soluble VCAM-1(sVCAM-1) were determined by sandwich ELISA both in normal healthy individuals (n = 114) and in patients with hypercholesterolemia (HC, n = 112) or ischemic heart disease (IHD, n = 38) to clarify the significance of the soluble forms of the adhesion molecules in the development of atherosclerotic diseases. IHD patients, not HC patients, showed significant elevation of sICAM-1, but not of sVCAM-1, compared with controls in age and sex-matched subjects. In addition, multiple linear regression analysis showed that sICAM-1 was correlated only to the presence of IHD but not to age and lipids. Multiple logistic regression analysis revealed that sICAM-1 was the most powerful independent predictor of the presence of IHD. On the other hand, sVCAM-1, not sICAM-1, was positively correlated to age. Multiple linear regression analysis showed that age was the most powerful independent predictor of the level of sVCAM-1. These data suggest that sICAM-1 and sVCAM-1 are useful as indices of clinical manifestations of atherosclerosis and aging, respectively.
Atherosclerosis 1997 May
PMID:New indices of ischemic heart disease and aging: studies on the serum levels of soluble intercellular adhesion molecule-1 (ICAM-1) and soluble vascular cell adhesion molecule-1 (VCAM-1) in patients with hypercholesterolemia and ischemic heart disease. 986 51


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