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)

Because of structural similarities between low density lipoproteins (LDL) and lipoprotein (a) (Lp(a)), we have investigated the properties and the functional activities of oxidized Lp(a) and focused on whether oxidized Lp(a), like oxidized LDL, can induce monocyte differentiation and adhesion of monocytic cells to endothelial cells grown in culture. Oxidized Lp(a), prepared in vitro by cupric ion oxidation, gave absorption curves of conjugated dienes with a lag-phase of 61.7 +/- 6.6 min (mean +/- S.D.) as compared to 85.2 +/- 7.2 min (n = 6, P < 0.01) for oxidized LDL from the same donors and at equimolar concentrations. Degradation of oxidized 125I Lp(a) by the monocytic cell line U937 at 37 degrees C was 1.6 +/- 0.3 nmol/g of cell protein, significantly (P < 0.01) greater than the degradation of oxidized 125I-LDL, which was 1.15 +/- 0.2 nmol/g of cell protein. Equimolar concentrations of oxidized Lp(a) and LDL inhibited the growth of U937 by 82 +/- 8.2% and 64 +/- 7.1%, respectively, when compared with the effect (negligible) produced by native Lp(a) and LDL. In addition, equimolar concentrations of oxidized Lp(a) and LDL induced adhesion molecule, Mac-1 (CD 11b), expression in U937 by 64 +/- 7.1% and 58 +/- 6.1% (P > 0.05), respectively, of the effect produced by phorbol esters (PMA) (P < 0.01). U937 cells incubated with oxidized Lp(a) and LDL, showed an adherence to cultured endothelial cells at 42 +/- 5.2% and 34 +/- 4.8%, respectively (P < 0.05), of the adherence shown by the same cells activated by PMA (P < 0.01). Our results suggest that oxidized Lp(a) like oxidized LDL plays an important role in the development of atherogenesis by inducing adhesion of monocytes to the arterial intimal and by stimulating intimal monocytes to differentiate into macrophages.
Atherosclerosis 1996 Jun
PMID:Oxidized lipoprotein (a) induces cell adhesion molecule Mac-1 (CD 11b) and enhances adhesion of the monocytic cell line U937 to cultured endothelial cells. 878 41

Decreased nitric oxide (NO) activity, the formation of reactive oxygen species, and increased endothelial expression of the redox-sensitive vascular cell adhesion molecule 1 (VCAM-1) gene in the vessel wall are early and characteristic features of atherosclerosis. To explore whether these phenomena are functionally interrelated, we tested the hypothesis that redox-sensitive VCAM-1 gene expression is regulated by a NO-sensitive mechanism. In early passaged human umbilical vein endothelial cells and human dermal microvascular endothelial cells, the NO donor diethylamine-NO (DETA-NO, 100 microM) reduced VCAM-1 gene expression induced by the cytokine tumor necrosis factor alpha (TNF-alpha, 100 units/ml) at the cell surface level by 65% and intracellular adhesion molecule 1 (ICAM-1) gene expression by 35%. E-selectin gene expression was not affected. No effect on expression of cell adhesion molecules was observed with DETA alone. Moreover, DETA-NO suppressed TNF-alpha-induced mRNA accumulation of VCAM-1 and TNF-alpha-mediated transcriptional activation of the human VCAM-1 promoter. Conversely, treatment with NG-monomethyl-L-arginine (L-NMMA, 1 mM), an inhibitor of NO synthesis, augmented cytokine induction of VCAM-1 and ICAM-1 mRNA accumulation. By gel mobility shift analysis, DETA-NO inhibited TNF-alpha activation of DNA binding protein activity to the VCAM-1 NF-kappa B like binding sites. Peroxy-fatty acids such as 13-hydroperoxydodecanoeic acid (linoleyl hydroperoxide) may serve as an intracellular signal for NF-kappa B activation. Using thin layer chromatography, DETA-NO (100 microM) suppressed formation of this metabolite, suggesting that DETA-NO modifies the reactivity of oxygen intermediates in the vascular endothelium. Through this mechanism, NO may function as an immunomodulator of the vessel wall and thus mediate inflammatory events involved in the pathogenesis of atherosclerosis.
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PMID:Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. 879 63

Adhesion molecules have been demonstrated immunohistochemically on smooth muscle cells in atherosclerotic plaques. In endothelial cells cytokines are potent modulators of adhesion molecule expression. We therefore investigated the effects of cytokines on adhesion molecule expression on cultured human coronary and pulmonary smooth muscle cells by cell ELISA and confocal microscopy. Human coronary and pulmonary smooth muscle cells expressed ICAM-1 and VCAM-1 but not E-selectin. ICAM-1 expression was upregulated by TNF alpha, Il-1 beta and IFN-gamma. VCAM-1 expression was increased by TNF alpha and weakly by Il-1 beta, IFN-gamma had no effect on VCAM-1 expression. Cytokine effects on ICAM-1 and VCAM-1 were based on de novo synthesis. These results demonstrate that cytokines regulate ICAM-1 and VCAM-1 expression on human coronary and pulmonary smooth muscle cells. These effects may play an important role in the immune mechanisms in atherosclerosis.
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PMID:Modulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 on human coronary smooth muscle cells by cytokines. 882 78

The intercellular adhesion molecule (ICAM) 1 is an Ig-like cell adhesion molecule expressed by several cell types, including leukocytes and endothelial cells. It can be induced in a cell-specific manner by several cytokines, for example, tumor necrosis factor-alpha, interleukin-1, and interferon-gamma, and inhibited by glucocorticoids. Its ligands are the membrane-bound integrin receptors LFA-1 and Mac-1 on leukocytes, CD43, the soluble molecule fibrinogen, the matrix factor hyaluronan, rhinoviruses, and Plasmodium falciparum malaria-infected erythrocytes. ICAM-1 expression is predominantly transcriptionally regulated. The ICAM-1 promoter contains several enhancer elements, among them a novel kappa B element which mediates effects of 12-O-tetradecanoylphorbol-13-acetate, interleukin-1, lipopolysaccharide, tumor necrosis factor-alpha, and glucocorticoids. Expression regulation is cell specific and depends on the availability of cytokine/hormone receptors, signal transduction pathways, transcription factors, and posttranscriptional modification. ICAM-1 plays a role in inflammatory processes and in the T-cell mediated host defense system. It functions as a costimulatory molecule on antigen-presenting cells to activate MHC class II restricted T-cells, and on other cell types in association with MHC class I to activate cytotoxic T-cells. ICAM-1 on endothelium plays an important role in migration of (activated) leukocytes to sites of inflammation. ICAM-1 is shed by the cell and detected in plasma as sICAM-1. Regulation and significance of sICAM-1 are as yet unclear, but sICAM-1 is increased in many pathological conditions. ICAM-1 may play a pathogenetic role in rhinovirus infections. Derangement of ICAM-1 expression probably contributes to the clinical manifestations of a variety of diseases, predominantly by interfering with normal immune function. Among these are malignancies (e.g., melanoma and lymphomas), many inflammatory disorders (e.g., asthma and autoimmune disorders), atherosclerosis, ischemia, certain neurological disorders, and allogeneic organ transplantation. Interference with ICAM-1 leukocyte interaction using mAbs, soluble ICAM-1, antisense ICAM-1 RNA, and in the case of melanoma mAb-coupled immunotoxin, may offer therapeutic possibilities in the future. Integration of knowledge concerning membrane-bound and soluble ICAM-1 into a single functional system is likely to contribute to elucidating the immunoregulatory function of ICAM-1 and its pathophysiological significance in various disease entities.
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PMID:Intercellular adhesion molecule-1. 883 67

Cigarette smoking is clearly linked with increased incidence of atherosclerosis and cardiovascular disease. The adherence of blood monocytes to the endothelium, followed by their migration beneath the endothelium, are initiating events in the formation of foam cells, promoting atherogenesis. We show that cigarette smoke condensate (CSC)-induced surface expression of a subset of cell adhesion molecules (CAM) [intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), and vascular cell adhesion molecule 1 (VCAM-1)] in human umbilical vein endothelial cells (HUVEC) is associated with an increase in the binding activity of nuclear transcription factor NF-kappa B to the consensus motif common to the CAM genes. Furthermore, CSC (25 microgram/ml) both increases the rate of transendothelial migration of vitamin D3-differentiated monocyte-like cells across the HUVEC monolayer by 200% and causes an approximately 10-fold increases in the phosphorylation of platelet endothelial CAM (PECAM-1), an adhesion molecule located at intercellular junctions and involved in endothelial cell-cell adhesion. Our results show that CSC-induced activation of protein kinase C in endothelial cells initiates a signaling pathways, leading to heightened binding of NF-kappa B to specific DNA sequences, which in turn increases surface expression of the subset of CAMs. Furthermore, our studies demonstrate a link between the phosphorylation of PECAM-1 and the migration of blood monocytes across vascular endothelium.
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PMID:Cigarette smoke condensate-induced adhesion molecule expression and transendothelial migration of monocytes. 892 67

Circulating levels of the adhesion molecule P-selectin (CD62P) are increased in the plasma of patients with atherosclerosis, but its relationship to the anatomical location of symptomatic disease or extent of symptomatic disease is unknown. The influence of the risk factors for atherosclerosis on soluble P-selectin is also unclear. To clarify these questions we analysed plasma samples from 170 patients with symptomatic peripheral vascular disease and 119 asymptomatic controls who were, as a group, age- and sex-matched. Soluble P-selectin (ELISA) was increased in 83 patients with symptomatic disease of the iliac and/or femoral arteries alone (P < 0.05, ANOVA) but not in 37 patients with symptomatic carotid artery disease alone compared with controls. Soluble P-selectin was equally raised in 120 patients with disease at one arterial site and in 50 patients with disease at two or more arterial sites (both P < 0.05) compared with controls. Smoking and atherosclerosis were both independent predictors of raised soluble P-selectin. We conclude that increased soluble P-selectin may have value as a marker of peripheral vascular disease of the iliac and/or femoral arteries in group comparisons only, as the poor discrimination and wide variation of data make comparisons at the individual level difficult.
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PMID:Soluble P selectin in peripheral vascular disease: relationship to the location and extent of atherosclerotic disease and its risk factors. 903 60

Monocyte adhesion to the arterial wall is a key event in the atherosclerotic process. We studied the interactions between human coronary arterial intimal smooth muscle cells (SMCs) and monocytes by examining (i) whether SMCs mediate monocyte adhesion when stimulated by oxidatively modified low density lipoprotein (LDL) or by the cytokines TNF alpha and IL-1, and (ii) the role of the adhesion molecules VCAM-1 and ICAM-1 (vascular cell and intercellular adhesion molecule, respectively) in this process. Preincubation of SMCs with both TNF alpha and IL-1 caused a significant 2-fold increase in VCAM-1 and ICAM-1 expression and a more than 9-fold increase in monocyte adhesion. The latter was significantly inhibited (by 1/3) by neutralising antibodies to VCAM-1 and ICAM-1. Modified LDL also induced a significant 3-fold increase in monocyte adhesion to SMCs, but did not induce VCAM-1 or ICAM-1 expression, nor was this adhesion inhibited by neutralising antibodies to VCAM-1 or ICAM-1. Oxidatively modified LDL, like the proinflammatory cytokines TNF alpha and IL-1, has the ability to enhance monocyte adhesion to human SMCs in vitro. LDL-induced monocyte adhesion to SMCs is distinct from that induced by TNF alpha and IL-1 in its lack of dependence on the classical adhesion pathways involving smooth muscle VCAM-1 and ICAM-1. SMCs are identified as a new cell population which may play an active role in recruiting monocytes to the arterial intima and atherosclerotic plaque.
Atherosclerosis 1996 Dec 20
PMID:Modified low density lipoprotein and cytokines mediate monocyte adhesion to smooth muscle cells. 912 6

Low-density lipoprotein (LDL) is a well-established risk factor for atherosclerosis. When endothelial cells are incubated with this lipoprotein in pathophysiologic amounts, the cells are activated. Among the documented cellular responses to LDL is increased recruitment of monocytes, which are believed to play a major role in promoting intimal plaque formation. The findings presented here link an atheogenic lipoprotein, LDL, with the induction of an adhesion molecule important in atherogenesis Human LDL induces the vascular cell adhesion molecule-1 (VCAM-1) transcriptionally with an increase in mRNA levels through activation of the VCAM promoter. This effect is blocked by anti-VCAM antibodies. After a 2-day incubation in LDL, the binding of NF-kappa B, which is believed to be a key oxidative-stress sensor for VCAM regulation, remains at basal level. In contrast, the binding activities of AP-1 and GATA, on the other hand, are increased by LDL. Thus, a component of LDL-enhanced endothelial recruitment of monocytes is attributed to VCAM-1 expression, which appears to be mediated through AP-1 and GATA. These data identify LDL as a VCAM-inducer possibly distinct from cytokines and endotoxin.
Atherosclerosis 1996 Dec 20
PMID:Induction of vascular cell adhesion molecule-1 by low-density lipoprotein. 912 8

T-cells and monocytes are the first cells infiltrating the arterial intima during the early stages of atherogenesis. Recently our laboratory has provided evidence that T-cells isolated from atherosclerotic intima reacts against heat shock protein 60 (Hsp60). Transmigration of activated T-cells into the intima is mediated by adhesion molecules (ICAM-1; VCAM-1; ELAM-1) expressed on activated endothelial cells. Here we studied the potential of cytokines (TNF-alpha, IFN-gamma, IL-1). Escherichia coli lipopolysaccharide (LPS), native and oxidized low-density lipoprotein (LDL; oxLDL) and high temperature to induce adhesion molecules as well as Hsp60 and Hsp70 expression in human endothelial cells (EC). On Northern blots, a strong signal for ICAM-1, VCAM-1 and ELAM-1 was detected after 4 h, which thereafter declined, but did not reach the basal level of untreated control cells. Heat shock induced the expression of Hsp60 and Hsp70 but not of adhesion molecules. EC were cultivated in serum-free medium, which led to the expression of adhesion molecule transcripts. Addition of LDL or oxLDL to these ECs did not alter the expression of these transcripts. The production of adhesion molecule proteins was analysed by flow cytometry. In human venous endothelial cells (HVEC) and human arterial endothelial cells (HAEC) ICAM-1 and VCAM-1 production was permanently highly induced, whereas the high level of ELAM-1 production at 4 h disappeared after 24 h. Furthermore, only HAEC, but not HVEC, produced ICAM-1, VCAM-1 and ELAM-1 after stress by moderately and highly oxLDL. LDL and oxLDL did not induce the production of Hsp60 and Hsp70. The present study demonstrates the co-expression of Hsp60 and adhesion molecules in arterial and venous EC in response to cytokine and LPS exposure, and that oxLDL is an efficient inducer of adhesion molecules in arterial EC and not in venous EC. These features provide the prerequisites for a cellular immune reaction against Hsp60 expressed by stressed EC in the initial stages of atherosclerosis.
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PMID:Co-expression of ICAM-1, VCAM-1, ELAM-1 and Hsp60 in human arterial and venous endothelial cells in response to cytokines and oxidized low-density lipoproteins. 925 Apr

Red blood cells (RBC) from patients with diabetes mellitus exhibit an increased propensity to adhere to cultured human umbilical vein endothelial cells (HUVEC) as a result of interaction of advanced glycation end products with their counter receptors, contributing to the pathogenesis of vascular complications. We determined whether the interaction of diabetic RBC with HUVEC induced cellular oxidant stress that would culminate in adherence and diapedesis of monocytes, these being initiating events in endothelial injury and atherogenesis. We show that the adherence of diabetic RBC (2% hematocrit), but not normal RBC, to HUVEC results in a fourfold increase in the production of lipid peroxides. Furthermore, diabetic RBC-induced oxidant stress causes a sixfold increase in platelet endothelial cell adhesion molecule-1 (PECAM-1) phosphorylation and doubles transendothelial migration of monocyte-like HL-60 cells; both are blocked by antioxidants and protein kinase C (PKC) inhibitors. Our results show that the adherence of diabetic RBC to endothelial cells initiates a cascade of cellular events resulting in PKC activation, causing PECAM-1 phosphorylation and concomitant transendothelial migration of monocytes. The increased diapedesis of monocytes, brought about by the interaction of diabetic RBC across vascular endothelium, may play an important role in accelerated atherosclerosis and cardiovascular disease in diabetics.
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PMID:Diabetic RBC-induced oxidant stress leads to transendothelial migration of monocyte-like HL-60 cells. 927 91


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