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)

Gallates (gallic acid esters) belong to the class of phenolic compounds, which are abundant in red wine. In this study, we show that gallates can inhibit cytokine-induced activation of nuclear factor kappaB (NF-kappaB) and thereby reduce expression of endothelial-leukocyte adhesion molecules in cultured human umbilical vein endothelial cells (HUVECs). Pretreatment of HUVECs with ethyl gallate (3 to 10 micromol/L) significantly suppressed interleukin-1alpha (IL-1alpha)- or tumor necrosis factor-alpha (TNF-alpha)- induced mRNA and cell-surface expression of vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin, which was associated with reduced adhesion of leukocytes to HUVECs. Gel shift assays with the NF-kappaB consensus sequence showed the decreased densities of the shifted bands in gallate-treated HUVECs. Furthermore, gallate pretreatment inhibited cytokine-induced transcription of a fusion gene, which consisted of 4 repeats of the NF-kappaB consensus sequence and the luciferase reporter gene. Immunoblot analysis of nuclear extracts and whole-cell lysates demonstrated the decreased amounts of NF-kappaB p65 in nuclei but equal amounts of inhibitor-kappaBalpha (I-kappaBalpha) in whole-cell lysates of ethyl gallate-treated HUVECs. Incubation of the nuclear extracts from cytokine-activated HUVECs with ethyl gallate did not affect the NF-kappaB shifted bands induced by cytokines in gel shift assays. Taken together, these data demonstrate that ethyl gallate can inhibit cytokine-induced nuclear translocation of NF-kappaB p65 by way of a mechanism independent of I-kappaBalpha degradation and thereby suppress expression of VCAM-1, ICAM-1, and E-selectin, which was associated with reduced adhesion of leukocytes. These results in vitro demonstrate that gallates can exhibit anti-inflammatory properties by blocking activation of NF-kappaB and suggest that these natural compounds, abundant in red wine, may play important roles in the prevention of atherosclerosis and inflammatory responses in vivo.
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PMID:Gallates inhibit cytokine-induced nuclear translocation of NF-kappaB and expression of leukocyte adhesion molecules in vascular endothelial cells. 1036 71

In this study, the effect of low density lipoproteins (LDL) on the ability of the vascular endothelium to respond to vascular cell adhesion molecule 1 (VCAM-1) activation by a cytokine was investigated. After a 4-day pre-exposure to 240 mg/dl of LDL, human umbilical vein endothelial cells (HUVECs) were hyperresponsive to minute amounts of interleukin 1 alpha (IL-1 alpha) as demonstrated by an augmentation of VCAM-1 gene expression. Furthermore, in response to LDL exposure, endothelial recruitment of monocytes induced by minute amounts of IL-1 alpha was increased. This enhancing effect was blocked by an anti-VCAM antibody. The increased response appears not to be due to changes in IL-1 binding affinity or induction of endogenous IL-1 alpha. Transient transfection of HUVECs with a reporter driven by the VCAM promoter showed that LDL increased cellular response to IL-1 alpha by 46%. LDL itself does not increase NF-kappa B binding in endothelial cells (ECs). However, after a 2-day LDL incubation, NF-kappa B binding could be induced by over 63% with a very low dose of IL-1 alpha. IL-1 alpha at this dose (which activates NF-kappa B, but not AP-1) also enhanced LDL-activated AP-1 binding. This cross-enhanced effect may be an important intracellular signaling mechanism for EC activation. The results from this study provide new clues to understanding the mechanisms governing combined risk factors for atherosclerosis.
Atherosclerosis 1999 Jun
PMID:Low-density lipoprotein augments interleukin-1-induced vascular adhesion molecule expression in human endothelial cells. 1040 96

Expression of 15-lipoxygenase (15-LO) is induced over 100-fold in early fatty streak lesions. 15-LO activity leads to the production of specific lipid hydroperoxides, which can have major effects on the expression of proinflammatory genes involved in atherogenesis. We have used retrovirus-mediated gene transfer to achieve stable high expression of 15-LO in human endothelial ECV304 cells. These cells were used to study the effects of 15-LO on the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), activation of nuclear factor kappa B (NF-kappaB), and T-cell adhesion on endothelial cells. NF-kappaB activation was greatly potentiated by increased 15-LO activity in the stably transduced cells, and both VCAM-1 and ICAM-1 were significantly induced in these cells in response to tumor necrosis factor-alpha (TNF-alpha) and phorbol 12-myristate 13-acetate (PMA) stimulation, as studied by flow cytometry. The induction of ICAM-1 was sensitive to antioxidants in a dose-dependent manner. The adherence of Jurkat T cells on the 15-LO-expressing endothelial cells was markedly induced after PMA stimulation. These results indicate that 15-LO activity may be involved in the early pathogenesis of atherosclerosis by inducing VCAM-1 and ICAM-1 expression and by increasing T-cell adhesion on the endothelium.
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PMID:High expression of human 15-lipoxygenase induces NF-kappaB-mediated expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and T-cell adhesion on human endothelial cells. 1122 35

Leukocyte infiltration in atherosclerosis has been extensively investigated by using histological techniques on fixed tissues. In this study, intravital microscopic observations of leukocyte recruitment in the aorta of atherosclerotic mice were performed. Interactions between leukocytes and atherosclerotic endothelium were highly transient, thereby limiting the ability for rolling leukocytes to firmly adhere. Leukocyte rolling was abolished by function inhibition of P-selectin (P<0.001, n=8), whereas antibody blockage of E-selectin (n=10) decreased rolling leukocyte flux to 51 +/- 9.9% (mean+/-SE, P<0.01) and increased leukocyte rolling velocity to 162 +/- 18% (P<0.01) of pretreatment values. Notably, function inhibition of the integrin alpha(4) subunit (n=5) had no effect on rolling flux (107+/-25%, P=0.782) or rolling velocity (89+/-6.1%, P=0.147), despite endothelial expression of vascular cell adhesion molecule 1 (VCAM-1). Leukocytes interacting with atherosclerotic endothelium were predominantly neutrophils, because treatment with antineutrophil serum decreased rolling and neutrophil counts in peripheral blood to the same extent. In conclusion, we present the first direct observations of atherosclerosis in vivo. We show that transient dynamics of leukocyte-endothelium interactions are important regulators of arterial leukocyte recruitment and that leukocyte rolling in atherosclerosis is critically dependent on the endothelial selectins. This experimental technique and the data presented introduce a novel perspective for the study of pathophysiological events involved in large-vessel disease.
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PMID:Direct viewing of atherosclerosis in vivo: plaque invasion by leukocytes is initiated by the endothelial selectins. 1134 83

Porphyromonas gingivalis is an oral pathogen that has recently been associated with chronic inflammatory diseases such as atherosclerosis. The strength of the epidemiological associations of P. gingivalis with atherosclerosis can be increased by the demonstration that P. gingivalis can initiate and sustain growth in human vascular cells. We previously established that P. gingivalis can invade aortic, heart, and human umbilical vein endothelial cells (HUVEC), that fimbriae are required for invasion of endothelial cells, and that fimbrillin peptides can induce the expression of the chemokines interleukin 8 and monocyte chemotactic protein. In this study, we examined the expression of surface-associated cell adhesion molecules on endothelial cells in response to P. gingivalis infection by fluorescence-activated cell sorting FACS analysis and confocal microscopy. Coculture of HUVEC with P. gingivalis strain 381 or A7436 resulted in the induction in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and P- and E-selectins, which was maximal at 48 h postinfection. In contrast, we did not observe induction of ICAM-1, VCAM-1, or P- or E-selectin expression in HUVEC cultured with the noninvasive P. gingivalis fimA mutant DPG3 or when P. gingivalis was incubated with fimbrillin peptide-specific anti-sera prior to the addition to HUVEC. Furthermore, the addition of a peptide corresponding to the N-terminal domain of fimbrillin to HUVEC resulted in an increase in ICAM-1, VCAM-1, and P- and E-selectins, which was maximal at 48 h and similar to that observed for live P. gingivalis. Treatment of P. gingivalis-infected HUVEC with cytochalsin D, which prevented P. gingivalis invasion, also resulted in the inhibition of ICAM-1, VCAM-1, or P- and E-selectin expression. Taken together, these results indicate that active P. gingivalis invasion of HUVEC mediated via the major fimbriae stimulates surface-associated cell adhesion molecule expression. Stimulation of adhesion molecules involved in the recruitment of leukocytes to sites of inflammation by P. gingivalis may play a role in the pathogenesis of systemic inflammatory diseases associated with this microorganism, including atherosclerosis.
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PMID:Fimbria-dependent activation of cell adhesion molecule expression in Porphyromonas gingivalis-infected endothelial cells. 1174 91

The diabetic vasculopathy is one of the major complications responsible for the high incidence of arteriopathy, coronary ischemia and renal failure. Several hypothesis have been formulated to explain the vascular abnormalities. We recently showed that advanced glycation end products (AGE) have a pivotal role in the genesis of vascular dysfunction. AGE bind to a receptor (RAGE) present on endothelial cells. AGE binding to RAGE produced an oxidant stress and diminished vascular barrier function, increased vascular permeability, enhanced the expression of vascular cell adhesion molecule 1 (VCAM-1). VCAM-1 expression on endothelial cell and increased expression of CD11b CD18 on monocytes may facilitate monocyte emigration and can represent one of the initial steps of vascular alteration. In diabetic animals or in ApoE null diabetic mice which developed atherosclerosis, the infusion of recombinant RAGE prepared in insect cells was studied. Recombinant RAGE administration corrected vascular hyperpermeability and prevented the development of atherosclerosis in the animals.
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PMID:Blood cells and vascular cell interactions in diabetes. 1179 Aug 70

Increased levels of triglyceride-rich lipoproteins provoke lipid accumulation in the artery wall, triggering early inflammatory responses central to atherosclerosis like endothelial adhesion molecule expression. The endogenous mechanisms limiting such reactions remain poorly defined. Lipoprotein lipase (LPL) plays a central role in lipid metabolism by hydrolyzing triglyceride rich lipoproteins and releasing fatty acids. We found that LPL treatment reversed tumor necrosis factor alpha and very low-density lipoprotein (VLDL)-stimulated endothelial vascular cell adhesion molecule 1 (VCAM1) induction and VCAM1 promoter responses, thus recapitulating effects reported with synthetic peroxisome proliferator-activated receptor (PPAR) agonists. In fact, these LPL effects on VCAM1 were absent in endothelial cells isolated from PPAR alpha-deficient mice. This finding suggests a novel antiinflammatory role for LPL. Further studies reveal specificity for PPAR activation through lipolysis in regards to lipoprotein substrate (VLDL >> LDL > HDL), PPAR isoform (PPAR alpha >> PPAR delta > PPAR gamma), and among fatty acid-releasing lipases. These PPAR responses required intact LPL catalytic activity. In vivo, transgenic mice overexpressing LPL had increased peroxisome proliferation, but not in the genetic absence of PPAR alpha. Although human plasma possesses minimal PPAR alpha activation despite containing abundant free fatty acids, marked PPAR alpha activation is seen with human plasma after LPL is added in vitro or systemically released in vivo. These data suggest a previously uncharacterized pathway in which the key lipolytic enzyme LPL can act on circulating lipoproteins to generate PPAR alpha ligands, providing a potentially important link between lipoprotein metabolism and distal PPAR alpha transcriptional effects.
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PMID:Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. 1260 19

Atherosclerosis is a major complication of diabetes. Up to 16 weeks of age, the db/db mouse is insulin-resistant and hyperglycemic and is a good model of Type 2 diabetes. After approximately 16 weeks of age, the mice develop pancreatic beta cell failure that can progress to a Type 1 diabetes phenotype. We have previously shown that glucose increases production of endothelial 12/15 lipoxygenase (12/15LO) products in vitro. In young 10-week-old Type 2 diabetic db/db mice, we found significant elevations in levels of urinary 12/15LO products, 12S-hydroxyeicosatetraenoic acid (12S-HETE) and 13S-hydroxyoctadecaenoic acid (13S-HODE) in vivo compared with C57BLKS/J mice. Using isolated primary aortic endothelial cells (ECs) from db/db mice and WEHI78/24 mouse monocyte cells in static adhesion assays, we found increased WEHI monocyte adhesion to db/db ECs (14 +/- 2 monocytes/field for db/db ECs versus 4 +/- 1 monocytes/field for C57BLKS/J ECs, p < 0.002). Thus, ECs from db/db mice appear to be "pre-activated" to bind monocytes. Analysis of db/db ECs revealed a 2-fold elevation in 12/15LO protein compared with C57BLKS/J EC. To determine that 12/15LO products were responsible for the increased monocyte adhesion observed with db/db ECs, we inhibited expression of murine 12/15LO using either an adenovirus expressing a ribozyme to 12/15LO (AdRZ) or with the 12/15LO inhibitor cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate. Treatment of db/db ECs for 48 h with AdRZ or 4 h with 10 microm cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate significantly reduced monocyte adhesion to db/db endothelium (p < 0.009). Thus, inhibition of the murine 12/15LO in db/db mice significantly reduced monocyte/endothelial interactions. We also found that adhesion of monocytes to diabetic db/db ECs was mediated by interactions of alpha4beta1 integrin on monocytes with endothelial vascular cell adhesion molecule 1 and connecting segment 1 fibronectin and interactions of beta2 integrins with endothelial intercellular adhesion molecule 1. In summary, regulation of the 12/15LO pathway is important for mediating early vascular changes in diabetes. Modulation of the 12/15LO pathway in the vessel wall may provide therapeutic benefit for early vascular inflammatory events in diabetes.
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PMID:Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice. 1273 8

Monocyte-endothelial adhesion plays an important role in monocyte trafficking and hence is important for immune responses and pathogenesis of inflammatory diseases including atherosclerosis. The cross-talk between different integrins on monocytes may be crucial for a coordinated regulation of the cellular adhesion during the complex process of transendothelial migration. By using monoclonal antibodies and recombinant intercellular adhesion molecule 1 (ICAM-1) to engage lymphocyte function-associated antigen 1 (LFA-1) on monocytic cells, we found that the cellular adhesion to vascular cell adhesion molecule 1 (VCAM-1) mediated by very late antigen 4 (VLA-4) was suppressed after this treatment and the suppression depended on the presence of reactive oxygen species (ROSs). Inhibition of production of ROSs through the use of inhibitor of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, but not inhibitors of mitochondrial electron transport chain or xanthine oxidase, revealed that this suppression on VLA-4-mediated cellular binding was mediated by ROSs produced by phagocyte NADPH oxidase. Activation of phosphoinositol-3 kinase and Akt appears to mediate this NADPH oxidase activation through p47phox phosphorylation and Rac-1 activation. Our results provide a novel pathway in which ROSs play a critical role in integrin cross-talk in monocytes. This signaling pathway may be important for cellular transition from firm arrest to diapedesis during monocyte trafficking.
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PMID:Ligation of lymphocyte function-associated antigen-1 on monocytes decreases very late antigen-4-mediated adhesion through a reactive oxygen species-dependent pathway. 1530 72

Atherosclerosis is a complex disease process in which monocytes and lymphocytes are recruited from the blood into the arterial intima. Mouse models of atherosclerosis have been developed, carefully characterized and used to elucidate molecular mechanisms of atherosclerotic lesion formation. Deficiency of various chemokines, chemokine receptors and leukocyte adhesion molecules that are known to participate in mononuclear leukocyte emigration, such as monocyte chemoattractant protein-1 and its receptor chemokine (CC motif) receptor 2, CX3C chemokine receptor 1 and vascular cell adhesion molecule 1, results in decreased formation of atherosclerotic lesions. In these studies, analysis was usually limited to assessment of lesion size, cellular composition and histological features. An assumption is often made that leukocyte recruitment is diminished if a reduction in lesions is found in chemokine- or adhesion molecule-deficient animals. However, direct quantification of leukocyte recruitment to atherosclerotic lesions is lacking and there is a need for practical recruitment assays that have the potential to provide precise and novel insights. For example, insights may be gained to distinguish the contribution of chemokines, chemokine receptors and adhesion molecules to the recruitment, survival or proliferation of different leukocyte types in atherosclerotic lesions.
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PMID:Leukocyte recruitment to atherosclerotic lesions. 1530 1

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