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)

Chronic macrophage-mediated inflammation is central to atherosclerosis. A role of the monocyte chemotactic and activating C-C chemokine JE/monocyte chemotactic protein-1 has been proposed. However, the human C-X-C chemokines growth-regulated oncogene (GROalpha) and IL-8, and their shared receptor, CXCR-2, also can be expressed at sites of chronic inflammation. Because we detected CXCR-2 in the intima of human atherosclerotic lesions, we examined the role of leukocyte CXCR-2 expression in affecting lesion cellularity. Atherosclerosis-susceptible LDL receptor-deficient mice were irradiated, successfully repopulated with bone marrow cells that either lacked or expressed mIL-8RH (the homologue of CXCR-2), and fed an atherogenic diet for 16 wk. In recipients of mIL-8RH+/+ marrow, mIL-8RH colocalized with densely accumulated intimal MOMA-2 positive macrophages. In contrast, lesions in recipients of mIL-8RH-/- marrow lacked mIL-8RH, had little intimal MOMA-2 staining, and were less extensive. The mIL-8RH ligand KC/GROalpha was detected in the intima of all aortic atherosclerotic lesions. Thus, the capacity of leukocytes to express mIL-8RH, and associated intralesional expression of its ligands such as KC/GROalpha, mediated the intimal accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice.
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PMID:A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. 943 7

The integrin heterodimer CDllb/CD18 (alphaMbeta2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear-resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet alphallbbeta3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac-1-mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro, indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs.
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PMID:Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions. 1035 67

The participation of inflammatory cells in atherosclerosis is a well-known process that involves numerous molecules including chemotactic cytokines (chemokines) for their entry into the vessel wall. Although the C-C chemokine monocyte chemoattractant protein-1 and its receptor, CCR2, have been implicated in atherosclerosis, the role of the classic C-X-C chemokine, interleukin-8 (KC/growth-related oncogene alpha in mice) and its receptor CXCR2 has not been studied in the pathogenesis of atherosclerosis. Our research has shown that CXCR2 is strongly expressed on macrophages (Mphi) in atherosclerotic lesion. This CXCR2 expression is proatherogenic in that CXCR2 deficiency significantly reduces the progression of advanced atherosclerosis in mice. Although the mechanism still needs to be worked out, it appears that CXCR2 expression on lesion Mphi is essential for these cells to be retained in the lesion.
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PMID:Interleukin-8 and its receptor CXCR2 in atherosclerosis. 1085 10

Recent data suggest that angiotensin II AT1 receptor antagonists may be beneficial in the treatment of atherosclerosis. To clarify how AT1 receptor antagonists reduce atherosclerosis, the effect of irbesartan on atherosclerotic lesion development was determined in low-fat, chow-fed apolipoprotein (Apo) E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesion development after a 12-week treatment period (lesion size: irbesartan treated, 20,524 +/- 4,200 microm(2) vs. control, 99,600 +/- 14,500; 79.4% inhibition, p < 0.001). This effect was not due to an effect of irbesartan on lipoprotein levels because irbesartan slightly increased total cholesterol levels and decreased the ratio of Apo A-I relative to Apo B levels. Immunochemical analysis of the atherosclerotic lesions using the mac3 monoclonal antibody showed the presence of macrophages in the lesions of control mice, whereas sections from irbesartan-treated animals only showed occasional labeling in the lesion area. These data suggest that irbesartan inhibits monocyte/macrophage influx into the vessel wall. Therefore, expression levels of monocyte chemoattractant protein-1 (MCP-1), as well as other chemokines involved in macrophage infiltration into the lesion area, were measured in the aortic sinus of control and irbesartan-treated animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as MCP-1 immunostaining in the lesion area. This effect of irbesartan on MCP-1 occurred without an effect on CCR2, the receptor of MCP-1. Expression of macrophage inflammatory protein (MIP)-1alpha, another CC chemokine expressed in atherosclerotic lesions, was also reduced after irbesartan treatment, without effect on CCR3 and CCR5, the receptors of MIP-1alpha. Concomitantly, the expression of the angiogenic chemokines KC and MIP-2, which are functionally related to interleukin-8, were downregulated, whereas their shared receptor CXCR2 was upregulated. These data suggest that inhibition of the inflammatory component of lesion progression plays an important role in the inhibitory effect of AT1 receptor antagonists on atherosclerotic lesion formation.
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PMID:Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice. 1148 44

The accumulation of macrophages and T lymphocytes in vessel walls is a hallmark of atherogenesis. It has recently been demonstrated in mouse models of atherosclerosis that full disease potential is dependent on several regulators of leukocyte trafficking, including the chemokine monocyte chemotactic protein 1 (MCP-1) and the chemokine receptors CCR2 and CXCR2. A possible role for the chemokine receptor CCR5 in atherogenesis has been suggested by CCR5 expression on macrophages, T cells, coronary endothelial cells and aortic smooth muscle cells and by the presence of CCR5 ligands in atherosclerotic plaques. Moreover, individuals who are naturally deficient in CCR5 were reported to be at reduced risk for severe coronary artery disease (CAD) and early myocardial infarction (MI). To investigate whether CCR5 is pro-atherogenic in mice, we generated CCR5-deficient mice and crossed them with atherosclerosis-prone apoE-deficient mice. Although CCR5-deficient mice exhibit defects in induced macrophage trafficking, mean atherosclerotic lesion area did not differ significantly between apoE-deficient mice and apoE/CCR5-deficient mice after 16 weeks on a diet of normal chow. Ribonuclease protection assays (RPA) on RNA isolated from plaques from both apoE-deficient and apoE/CCR5-deficient animals showed strong signals for the macrophage marker F4/80 but no evidence for expression of prominent markers of T and B lymphocytes. These results indicate that the early stages of plaque formation in this model of lipid-mediated atherogenesis do not depend on CCR5.
Atherosclerosis 2003 Mar
PMID:CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice. 1261 65

T lymphocytes and monocytes/macrophages are the most abundant cells found in the atherosclerotic plaque. These cells can migrate towards the activated endothelium through the local release of chemotactic cytokines, or chemokines. Given the important role of leukocyte migration in atherosclerosis and the role of stress in mediating leukocyte trafficking, the present study examined the effects of an acute stressor on the redistribution of T cells (CD3+) and monocytes that express the chemokine receptors CCR5, CCR6, CXCR1, CXCR2, CXCR3, and CXCR4. Forty-four undergraduate students underwent a public speaking task. The acute stressor induced sympathetic cardiac activation, parasympathetic cardiac withdrawal, lymphocytosis, and monocytosis (all p<.001). Although the total number of T lymphocytes did not change, there was a selective increase in the number of circulating T cells expressing CXCR2, CXCR3, and CCR5. The ligands of these receptors are chemokines known to be secreted by activated endothelial cells. Analyses of individual differences in stress-induced responses demonstrated a positive relationship between sympathetic cardiac reactivity and mobilization of the various T cell subsets (.35<r<.56;p<.05). For the monocytes, all sub-populations increased in parallel with total monocyte numbers, with no relation to changes in sympathetic cardiac drive. These results indicate that acute stress induces a mobilization of T cells that are primed to respond to inflamed endothelium. Acute stressors may thus promote the recruitment of circulating immune cells into the sub-endothelia, and therefore accelerate atherosclerotic plaque formation and potentially contribute to the complications that follow acute stressful events. This mechanism may help explain the link between stress, reactivity, and cardiovascular disease.
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PMID:Acute stress evokes selective mobilization of T cells that differ in chemokine receptor expression: a potential pathway linking immunologic reactivity to cardiovascular disease. 1283 27

To investigate effects of supplementation of folic acid on the expression of adhesion molecules VCAM-1 in the aortas of rats with hyperhomocysteinemia. Thirty male SD rats (200 +/- 20 g) were invided into 3 groups (n = 10 for each group): control group(Control), high Met group(Met) and Met plus Folate group(Met + Folate), fed. for 45 days. Plasma Hcy levels were higher with the high-methionine diet (140.68 +/- 36.87 micromol/L vs 6.47 +/- 1.10 micromol/L in control rats) an effect which was reduced by folate. Respectively, the aortic expression of adhesion molecules VCAM-1 at protein and mRNA levels were higher in the Met groups than those in the control groups or the Met + Folate groups. A high methionine diet for 45 days was sufficient to induce hyperhomocysteinemia. Folate supplementation prevented elevation of Hcy levels in the blood, and reduced expression of the adhesion molecule VCAM-1. Hyperhomocysteinemia is now regarded as one of the important risk factors for cardiovascular and cerebralvascular disorders.[Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 38(15):1042-50.] Several plausible mechanisms for Hcy-induecd atherosclerosis have been proposed. These include endothelial dysfunction, enhancement of oxidative stress, reduction in NO bioavailability, and augmentation of thrombus formation.[Holven KB, Holm T, Aukrust P, et al. Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects . Am J Med 2001;110(7):536-42; Guba SC, Fonseca V, Fink LM. Hyperhomocysteinemia and thrombosis. Semin Thromb Hemost 1999;25(3):291-309.] However, the precise molecular mechanism is still unclear. Recent reports have suggested a role for inflammatory processes in the pathogenesis of atherosclerosis.[Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2(2):108-15.] Dysfunction of endothelial cells is the key process promoting inflammatory reactions. On injury, endothlial cells are capable of producing various cytokines that participate in inflammatory reactions in the arterial wall. Although results from in vitro studies suggest that Hcy, at pathophysiological concentrations, stimulates chemokine expression in vascular cells, it is unknown whether hyperhomocysteinemia can initiate similar changes, leading to enhanced momocyte adhesion/binding to the vascular endothelium in vivo.[Zeng X, Dai J, Remick DG, Wang X. Homocysteine mediated expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human monocytes. Circ Res 2003;93(4):311-20.] On the basis of the potential pathogenic role of chemokines in atherogenesis, the objective of the present study was to investigate that homocsteine may exert its effect in part though adhesion molecules VCAM-1 and that folic acid supplementation may downregulate these inflammatory responses. Male Sprague-Dawley rats (bred from animal centers of Tongji Medical College, Huazhong Science and Technology University) aged 8 weeks were divided into 3 groups(n=10 for each group) and maintained for 45 days on the following diets before the experiments: (1) regular diet; (2) high-metheionine diet, consisting of regular diet plus 1.7% methionine; and (3) high-methionine plus folate -rich diet, consisting of regular diet plus 1.7% methionine and 0.006% folate.[Boisvert WA, Curtiss LK, Terkeltaub RA. Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunol Res 2000;21(2-3):129-d37.] Plasma and serum samples wee colleced and stored at -80 degrees C after 45 days until analysis. The plasma homocysteine concentration of rats in three groups were determined by high-pressue liquid chromatography. To detect the endothelial expression of adhesion molecules VCAM-1, the thoracic aorta was isolated and dived into segments. These segments were immersion-fixed in 10% neutral-buffered formalin overlight and then embedded in paraffin. Sequential 5 mum paraffin-embedded cross sections were prepared. Immunohistochemical analyisis was performed to detect vascular cell adhesion molecule(VCAM)-1, The fixed cryosections were immediately blcked in 10% horse serum and phosphate baffered saline(PBS) at room temperature for 30 min. Goat polyclonal andibodies against rat VCAM-1(Santa Cruz Biotechnology) were diluted 1:100 in PBS and incubated with the cryosections for 1 h of room temperature. After three washes, the sections were incubated with biotin-conjugated rabbit anti-goat immunoglobulins(Dako) at 1:250 dilution in PBS. After three washes, the samples were mounted in 90% glycerol-PBS. Photographs were taken by use of a light microscope at a mignification of x200.
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PMID:Folic acid reduces adhesion molecules VCAM-1 expession in aortic of rats with hyperhomocysteinemia. 1618 51

We have previously reported (Dobreva, I., Waeber, G., Mooser, V., James, R. W., and Widmann, C. (2003) J. Lipid Res. 44, 2382-2390) that low density lipoproteins (LDLs) induce activation of the p38 MAPK pathway, resulting in fibroblast spreading and lamellipodia formation. Here, we show that LDL-stimulated fibroblast spreading and wound sealing are due to secretion of a soluble factor. Using an antibody-based human protein array, interleukin-8 (IL-8) was identified as the main cytokine whose concentration was increased in supernatants from LDL-stimulated cells. Incubation of supernatants from LDL-treated cells with an anti-IL-8 blocking antibody completely abolished their ability to induce cell spreading and mediate wound closure. In addition, fibroblasts treated with recombinant IL-8 spread to the same extent as cells incubated with LDL or supernatants from LDL-treated cells. The ability of LDL and IL-8 to induce fibroblast spreading was mediated by the IL-8 receptor type II (CXCR-2). Furthermore, LDL-induced IL-8 production and subsequent wound closure required the activation of the p38 MAPK pathway, because both processes were abrogated by a specific p38 inhibitor. Therefore, the capacity of LDLs to induce fibroblast spreading and accelerate wound closure relies on their ability to stimulate IL-8 secretion in a p38 MAPK-dependent manner. Regulation of fibroblast shape and migration by lipoproteins may be relevant to atherosclerosis that is characterized by increased LDL cholesterol levels, IL-8 production, and extensive remodeling of the vessel wall.
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PMID:Interleukin-8 secretion by fibroblasts induced by low density lipoproteins is p38 MAPK-dependent and leads to cell spreading and wound closure. 1625 Nov 88

Macrophage-mediated inflammation is central to atherogenesis. We have determined previously that the CXC chemokine receptor CXCR2 is involved in advanced atherosclerosis. We sought to determine whether one of the ligands of CXCR2, KC/GRO-alpha, can also modulate atherogenesis. KC/GRO-alpha(-/-) mice were generated and mated with the atherosclerosis-prone LDLR(-/-) mice. There was a significant reduction in atherosclerosis in mice lacking KC/GRO-alpha; however, this reduction was only approximately half that seen previously in mice lacking CXCR2 in the leukocyte. To determine whether CXCR2 is involved in the early formation of atherosclerosis, leukocyte-specific CXCR2(-/-) chimeric mice on LDLR(-/-) background were generated. Early fatty streak lesion formation in these mice was not affected by leukocyte CXCR2 deficiency whereas lesions were less developed in mice lacking leukocyte CXCR2 when atherosclerosis was allowed to progress to the intermediate stage. Macrophages were relatively sparse in the lesions of leukocyte CXCR2(-/-) mice despite robust MCP-1 expression. These studies indicate that KC/GRO-alpha/CXCR2 does not play a critical role in recruitment of macrophages into early atherosclerotic lesions but both arterial KC/GRO-alpha and leukocyte-specific CXCR2 expression are central to macrophage accumulation in established fatty streak lesions.
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PMID:Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. 1656 11

We have previously reported that L5, the most negatively charged subfraction of plasma low-density lipoprotein (LDL), induces mononuclear leukocyte (MNC) adhesion under flow conditions in vitro when endothelial cells are incubated with L5. The present study was undertaken to identify responsible adhesion molecules and chemokines. LDL isolated from patients with homozygous familial hypercholesterolemia was separated into five distinct subfractions by high-capacity ion-exchange chromatography. Differentially expressed mRNA between human umbilical vein endothelial cells (HUVEC) incubated (for 22h) with the earliest subfraction (L1: 20 microg/ml) and the latest and most negatively charged subfraction (L5: 20 microg/ml) was identified by DNA microarray analysis using three independent sets of RNA. mRNA consistently upregulated by L5 included VCAM-1 (2.3-fold) and CXC chemokines GRO-alpha (2.3), GRO-beta (4.6), IL-8 (2.5), ENA-78 (2.3), GRO-gamma (1.6) and GCP-2 (1.5). These results were validated by Northern analysis, semi-quantitative RT-PCR or ELISA. Blocking studies using monoclonal antibodies revealed that both primary capture and stable adhesion of MNC to HUVEC and human aortic endothelial cells (HAEC) incubated with L5 was mediated by VCAM-l/alpha4 integrin, whereas GRO and its receptor CXCR2 were involved in the stable adhesion of MNC to L5-treated HAEC.
Atherosclerosis 2007 May
PMID:L5, the most electronegative subfraction of plasma LDL, induces endothelial vascular cell adhesion molecule 1 and CXC chemokines, which mediate mononuclear leukocyte adhesion. 1702 86


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