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)

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

Atherosclerosis is an inflammatory disease of the vessel wall, characterized by the accumulation of leukocytes, especially macrophages and T-cells. Chemokines are small heparin-binding polypeptides, whose main function is to attract cells to the areas of developing inflammation. They function by ligating G-protein coupled chemokine receptors initiating different signaling cascades. In vivo and in vitro investigations showed that chemokines are produced by a variety of cells and play important roles in the development and progression of many physiological and pathological conditions including atherosclerosis. Chemokines such as MCP-1, MCP-4, MIP-1 and RANTES may mediate leukocyte trafficking to, and their retention in, the plaque while CXCL16 seems to fulfill the dual function of a chemokine and a scavenger receptor. Chemokine and chemokine receptor homologues are secreted by several viruses, which may also play a role in the pathogenesis of atherosclerosis. Expression levels and gene polymorphisms of some chemokines may become useful clinical markers of atherosclerosis and other cardiovascular diseases. Modulation of chemokines and chemokine receptors' expression as well as their signaling pathways may provide important anti-atherogenic strategies.
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PMID:Chemokines and atherosclerosis. 1511 30

This study investigated in prepubertal obese children (POC), compared with prepubertal lean children (PLC), a possible relation among plasma total homocysteine (tHcy)-an independent risk factor for future atherosclerosis-and MCP-1 and RANTES, two circulating chemokines inducing leukocyte transendothelial migration (TEM), implicated in the initial stages of the inflammatory part of the atherosclerotic process. Seventy-two POC were evaluated for circulating tHcy, MCP-1, and RANTES, and compared with 42 healthy PLC. The mean adjusted (for age, sex as well as log10total insulin, vitB12, folate, total cholesterol, HDL cholesterol, log10triglycerides, and log10glucose levels) differences in tHcy, MCP-1, and RANTES levels between PLC and POC were all significant [1.16 nmol/mL (P = 0.03), 26.6 pg/mL (P = 0.02), and 52.9 pg/mL (P = 0.03), respectively]. In PLC, but not in POC, tHcy levels were negatively associated with both circulating MCP-1 (B = -1.68, P = 0.007) and RANTES (B = -1.16, P = 0.01) after adjusting for age, sex, BMI, as well as log10total insulin, vitB12, folate, total cholesterol, HDL cholesterol, log10triglycerides, and log10glucose levels. In conclusion, in POC there is a lack, in contrast to PLC, of a possibly autoregulatory, negative association of elevated tHcy levels to increased MCP-1 and RANTES levels. This could contribute to future, homocysteine-induced atherosclerosis.
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PMID:Negative association between circulating total homocysteine and proinflammatory chemokines MCP-1 and RANTES in prepubertal lean, but not in obese, children. 1547 27

Viral and bacterial pathogens have long been suspected to affect atherogenesis directly. However, mechanisms linking innate immunity to chronic inflammatory diseases such as atherosclerosis are still poorly defined. Here we show that infection of primary human aortic smooth muscle cells (HAOSMC) with human cytomegalovirus (HCMV) leads to activation of the novel IkappaB kinase (IKK)-related kinase, Tank-binding kinase-1 (TBK1), a major effector of the cellular innate immune response. We demonstrate that part of the HCMV inflammatory response is most likely mediated via this novel kinase because the canonical IKK complex was only poorly activated upon infection of HAOSMC. An increase in TBK1 phosphotransferase activity led to a strong activation of the interferon regulatory factor (IRF)-3 transcription factor as measured by its C-terminal phosphorylation, dimerization, and DNA binding activity. In addition to TBK1, HAOSMC also express another IKK-related kinase isoform, IKKepsilon, albeit at a lower level. Nevertheless, both isoforms were required for full activation of IRF-3 by HCMV. The transcripts of proatherosclerotic genes Ccl5 (encoding for the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted)) and Cxcl10 (encoding for the chemokine IP-10 (interferon-gamma-inducible protein 10)) were induced in an IRF-3-dependent manner after HCMV infection of smooth muscle cells. In addition, cytokine arrays analysis showed that RANTES and IP-10 were the predominant chemokines present in the supernatant of HCMV-infected HAOSMC. Activation of the TBK1/IRF-3 pathway was independent of epidermal growth factor receptor and pertussis toxin-sensitive G protein-coupled receptor activation. Our results thus add additional molecular clues to a possible role of HCMV as a modulator of atherogenesis through the induction of a proinflammatory response that is, in part, dependent of an IKK-related kinase pathway.
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PMID:Roles of an IkappaB kinase-related pathway in human cytomegalovirus-infected vascular smooth muscle cells: a molecular link in pathogen-induced proatherosclerotic conditions. 1561 5

A role for infection and inflammation in atherogenesis is widely accepted. Arterial endothelium has been shown to express heat shock protein 60 (HSP60) and, since human (hHSP60) and bacterial (GroEL) HSP60s are highly conserved, the immune response to bacteria may result in cross-reactivity, leading to endothelial damage and thus contribute to the pathogenesis of atherosclerosis. In this study, GroEL-specific T-cell lines from peripheral blood and GroEL-, hHSP60-, and Porphyromonas gingivalis-specific T-cell lines from atherosclerotic plaques were established and characterized in terms of their cross-reactive proliferative responses, cytokine and chemokine profiles, and T-cell receptor (TCR) Vbeta expression by flow cytometry. The cross-reactivity of several lines was demonstrated. The cytokine profiles of the artery T-cell lines specific for GroEL, hHSP60, and P. gingivalis demonstrated Th2 phenotype predominance in the CD4 subset and Tc0 phenotype predominance in the CD8 subset. A higher proportion of CD4 cells were positive for interferon-inducible protein 10 and RANTES, with low percentages of cells positive for monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha, whereas a high percentage of CD8 cells expressed all four chemokines. Finally, there was overexpression of the TCR Vbeta5.2 family in all lines. These cytokine, chemokine, and Vbeta profiles are similar to those demonstrated previously for P. gingivalis-specific lines established from periodontal disease patients. These results support the hypothesis that in some patients cross-reactivity of the immune response to bacterial HSPs, including those of periodontal pathogens, with arterial endothelial cells expressing hHSP60 may explain the apparent association between atherosclerosis and periodontal infection.
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PMID:Characterization of heat shock protein-specific T cells in atherosclerosis. 1569 20

Mouse cytomegalovirus (MCMV) encodes two potential seven-transmembrane-spanning proteins with homologies to cellular chemokine receptors, M33 and M78. While these virus-encoded chemokine receptors are necessary for the in vivo pathogenesis of MCMV, the function of these proteins is unknown. Since vascular smooth muscle cell (SMC) migration is of critical importance for the development of atherosclerosis and other vascular diseases, the ability of M33 to promote SMC motility was assessed. Similar to human CMV, MCMV induced the migration of mouse aortic SMCs but not mouse fibroblasts. To demonstrate whether M33 was required for MCMV-induced SMC migration, we employed interfering-RNA technology to specifically knock down M33 expression in the context of viral infection. The knockdown of M33 resulted in the specific reduction of M33 protein expression and ablation of MCMV-mediated SMC migration but failed to reduce viral growth in cultured cells. Adenovirus vector expression of M33 was sufficient to promote SMC migration, which was enhanced in the presence of recombinant mouse RANTES (mRANTES). In addition, M33 promoted the activation of Rac1 and extracellular signal-related kinase 1/2 upon stimulation with mRANTES. These findings demonstrate that mRANTES is a ligand for this chemokine receptor and that the activation of M33 occurs in a ligand-dependent manner. Thus, M33 is a functional homologue of US28 that is required for MCMV-induced vascular SMC migration.
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PMID:Mouse cytomegalovirus M33 is necessary and sufficient in virus-induced vascular smooth muscle cell migration. 1605 70

Increased oxidative stress (SOX) has been reported in continuous ambulatory peritoneal dialysis (CAPD) patients, but its influence on beta-chemokine levels and progression of atherosclerosis remains unknown. We determined three distinct SOX markers: Cu/Zn superoxide dismutase (Cu/Zn SOD), total peroxide and autoantibodies against oxidized LDL (OxLDL-Ab); high sensitivity C-reactive protein (hs CRP); beta-chemokines: monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory proteins (CCL3 and CCL4) and regulated upon activation, normal T cell expressed and secreted (CCL5) and the intima-media thickness (IMT) values in CAPD patients both with and without cardiovascular disease (CVD) and healthy controls. CAPD patients both with and without CVD had significantly increased IMT (p<0.001 and <0.01), Cu/Zn SOD (both p<0.001) and CCL2 levels (p<0.001 and <0.01, respectively) as compared to controls. CCL4 (p<0.01) and hs CRP (p<0.05) were increased only in patients with CVD, whereas there were no differences in the total peroxide, OxLDL-Ab and CCL3 levels between patients and controls. CCL5 concentrations were significantly decreased in both patients subgroup (both p<0.001) versus controls. Multivariate analysis showed that age (p<0.001), male sex (p<0.01), CCL4 and CCL2 levels (both p<0.05) were the independent variables linked to IMT values. Our data suggest a possible role of enhanced beta-chemokine levels in the carotid atherosclerosis in patients treated with CAPD, in addition to age and male sex.
Atherosclerosis 2006 May
PMID:Carotid atherosclerosis is associated with enhanced beta-chemokine levels in patients on continuous ambulatory peritoneal dialysis. 1609 64

HIV patients are predisposed to the development of hypertriglyceridemia and hypercholesterolemia as a result of both viral infection and HIV infection therapy, especially the protease inhibitors. Chemokines and cytokines are present at sites of inflammation and can influence the nature of the inflammatory response in atherosclerosis. We investigated the correlation between biochemical variables and beta-chemokines (MIP-1alpha and RANTES) and the apolipoprotein E genotype in HIV-infected individuals. The apolipoproteins were measured by nephelometry. Triglycerides and total cholesterol were determined by standard enzymatic procedures. The beta-chemokines were detected by ELISA. The genetic category of CCR5 and apolipoprotein E were determined by PCR amplification and restriction enzymes. Immunological and virological profiles were assessed by TCD(4)+ and TCD(8)+ lymphocyte counts and viral load quantification. Positive correlations were found between apo E and CD(8)+ (p = 0.035), apo E and viral load (p = 0.018), MIP-1alpha and triglycerides (p = 0.039) and MIP-1a and VLDL (p = 0.040). Negative correlations were found between viral load and CD(4)+ (p = 0.05) and RANTES and CD(4)+ (p = 0.029). The beta-chemokine levels may influence lipid metabolism in HIV-infected individuals.
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PMID:The beta-chemokines MIP-1alpha and RANTES and lipoprotein metabolism in HIV-infected Brazilian patients. 1627 Jan 24

The pleiotropic effects of statin, including its anti-inflammatory effects, via chemokines may be independent of statin-induced cholesterol reduction. Therefore, we examined the effect of pitavastatin on cell proliferation and the association between chemokine receptors (CCR2 and CCR5) and their ligands, RANTES (regulated upon activation, normal T cell-expressed and secreted) and monocyte chemotactic protein-1 (MCP-1), in monocytes. Pitavastatin but not pravastatin inhibited cell proliferation in a dose-dependent manner and showed S-phase arrest associated with the downregulation of CCR2 and CCR5 expression in human monocytic tumor cells (U937 cells). Although the anti-proliferative effects of pitavastatin were not inhibited by lower concentrations of RANTES and MCP-1, overexpression of CCR2/CCR5 significantly blocked the anti-proliferation with a low concentration of RANTES or MCP-1. Pitavastatin upregulated p21(waf1) but not p27(kip1), and did not change the expression levels of cyclin D1 or cdk4. In addition, RANTES and MCP-1 upregulated cyclin D1 in the presence of pitavastatin. In conclusion, the anti-proliferative effect of pitavastatin, but not pravastatin, through the downregulation of CCR2/CCR5 may be a pleiotropic effect. This effect may be anti-atherogenic in monocytes.
Atherosclerosis 2006 Aug
PMID:Pitavastatin-induced downregulation of CCR2 and CCR5 in monocytes is associated with the arrest of cell-cycle in S phase. 1628 73

CC chemokines mediate mononuclear cell recruitment and activation in chronic inflammation. We have shown previously that gene transfer using recombinant adenoviruses, encoding a soluble CC chemokine-binding protein of vaccinia virus 35K, can dramatically reduce atherosclerosis and vein graft remodeling in apolipoprotein E knockout mice. In this study, we report the development of a membrane-bound form of 35K (m35K), tagged with GFP, which allows for localized, broad-spectrum CC chemokine blockade. In vitro experiments indicate that m35K-expressing cells no longer undergo CC chemokine-induced chemotaxis, and m35K-expressing cells can locally deplete the CC chemokines RANTES (CCL5) and MIP-1alpha (CCL3) from supernatant medium. This sequestration of CC chemokines can prevent chemotaxis of bystander cells to CC, but not CX(3)C chemokines. Intraperitoneal injection of mice with an adenovirus-encoding m35K leads to a significant (44%) decrease in leukocyte recruitment into the peritoneal cavity in a sterile peritonitis model. Intravenous adenovirus-encoding m35K delivery leads to m35K expression in hepatocytes, which confers significant protection against liver damage (75% reduction in liver enzymes) in a Con A-induced hepatitis model. In summary, we have generated a membrane-bound CC chemokine-binding protein (m35K) that provides localized broad-spectrum CC chemokine inhibition in vitro and in vivo. m35K may be a useful tool to study the role of CC chemokines in leukocyte trafficking and block the recruitment of monocytes in chronic inflammation.
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PMID:Membrane-bound CC chemokine inhibitor 35K provides localized inhibition of CC chemokine activity in vitro and in vivo. 1701 44


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