Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that epigallocatechin-3-gallate (EGCG), a major catechin found in green tea, plays a role in preventing the progression of atherosclerosis. Although EGCG has anti-atherogenic effects on vascular smooth muscle cells (VSMC), the molecular mechanisms associated with TNF-alpha-induced VSMC are not known with certainty. To determine whether EGCG has the capacity to modulate VSMC responses, cell cycle regulation and MMP-9 expression were examined in TNF-alpha-induced VSMC. Treatment with EGCG, which blocks the cell cycle in the G(1) phase, induced a down-regulation of cyclins and CDKs and an up-regulation in the expression of p21/WAF1, a CDK inhibitor, whereas the up-regulation of p27 by EGCG was not observed. Moreover, treatment with EGCG markedly increased the promoter activity of the p21/WAF1 gene. Immunoblot and deletion analysis results for the p21/WAF1 promoter showed that EGCG induced the expression of p21/WAF1 independent of the p53 pathway. Zymographic and immunoblot analyses showed that EGCG suppressed TNF-alpha-induced MMP-9 expression in a dose-dependent manner. Further experiments demonstrated that EGCG reduced the transcriptional activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), two important nuclear transcription factors that are involved in MMP-9 expression. Collectively, these results suggest that EGCG inhibits G(1) to S-phase cell cycle progress and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC.
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PMID:Epigallocatechin-3-gallate causes the p21/WAF1-mediated G(1)-phase arrest of cell cycle and inhibits matrix metalloproteinase-9 expression in TNF-alpha-induced vascular smooth muscle cells. 1570 69

Matrix metalloproteinases (MMPs) play an important role in many biological and pathological processes including tissue remodeling, wound healing, inflammation, atherosclerosis, and cancer. Numerous publications have supported the concept that activated MMP-2 enhances agonist-induced platelet aggregation and activated MMP-9 inhibits platelet aggregation. In this study, we demonstrated that the organomercurial compound, 4-aminophenyl mercuric acetate (APMA), which is routinely employed to activate latent MMPs at a concentration of 1000 microM, induces platelet aggregation at low concentration (5 microM) and inhibits agonist-induced platelet aggregation at concentrations >or= 50 microM. Activated MMP-2, MMP-1, and MMP-9, following removal of APMA by ultrafiltration through an anisotropic membrane, exert no independent effect on platelet aggregation. Acetylsalicylic acid and BAPTA inhibited APMA-induced platelet aggregation indicating that the APMA mediated pathway of platelet activation is dependent upon thromboxane and calcium signaling. Zinc chelation with 1,10-phenanthroline, which inhibits zinc-dependent proteins including metalloproteinases, also abrogated platelet functional responses to APMA. Additional studies will be required to clarify the mechanism of the biphasic effect of APMA on platelet aggregation.
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PMID:The organomercurial 4-aminophenylmercuric acetate, independent of matrix metalloproteinases, induces dose-dependent activation/inhibition of platelet aggregation. 1571 50

TL1A (VEGI/TNFSF15) is the ligand for DR3 (TNFRSF12) and is a newly identified member of the tumor necrosis factor superfamily (TNFSF). Previously, DR3 has been shown to have a role in atherogenesis through stimulation of matrix degrading enzymes including matrix metalloproteinase (MMP)-9. Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high-level expression of TL1A in regions rich in macrophage/foam cells. To investigate the role of TL1A and DR3 in the functioning of macrophage/foam cells in relation to atherogenesis, we have analyzed cellular events mediated by TL1A and DR3 in a human macrophage-like cell line, THP-1. Treatment of THP-1 cells with immobilized anti-DR3 monoclonal antibody in combination with IFN-gamma caused induction of pro-atherogenic cytokines/chemokines such as TNF-alpha, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-8. Treatment of THP-1 cells with recombinant TL1A in combination with IFN-gamma also caused induction of MMP-9 and IL-8. Furthermore, the expression of DR3 in peripheral blood monocytes was induced after atherogenic stimulation. These data suggest that TL1A and DR3 is involved in atherosclerosis via the induction of pro-inflammatory cytokines/chemokines and decreasing plaque stability by inducing extracellular matrix degrading enzymes.
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PMID:Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. 1576 Jun 79

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), beta-chemokines, increased oxidative stress (SOX) and inflammation have been implicated as important factors in atherosclerosis and vascular remodeling. We hypothesized the possible roles of beta-chemokines [monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins (MIP-1alpha, MIP-1beta) and regulated upon activation, normal T-cell expressed and secreted (RANTES)] as regulators of the metabolism of the vascular extracellular matrix in conditions of increased SOX in hemodialysis (HD) patients. We compared pre-dialysis levels of MMP-9/TIMP-1 system, beta-chemokines, Cu/Zn superoxide dismutase (Cu/Zn SOD) as a marker of SOX and C-reactive protein (CRP) as a marker of inflammation in HD patients with and without cardiovascular disease (CVD) to those of controls. HD patients, particularly those with CVD, showed a significant increase in values of Cu/Zn SOD, CRP, TIMP-1, TIMP-1/MMP-9 ratio, MCP-1 and MIP-1beta, whereas RANTES levels were lower than in the controls. The levels of MIP-1alpha as well as MMP-9 in all HD groups were similar to the controls. The positive correlations were observed between the MMP-9/TIMP-1 system and beta-chemokines, SOX and inflammation in whole HD group and in the subgroup with CVD. Multivariate analysis showed that the duration of dialysis followed by Cu/Zn SOD, MIP-1alpha and beta levels were the significant positive predictors of TIMP-1. In conclusion, our data show that MMP-9/TIMP-1 system and beta-chemokines could cooperate in conditions of elevated SOX, which ultimately predisposes hemodialysis patients to accelerated atherosclerosis.
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PMID:Circulating beta-chemokines and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system in hemodialyzed patients--role of oxidative stress. 1589 74

Hepatocyte growth factor (HGF) is a potent regeneration factor for endothelial and epithelial cells, and has also been shown to modulate extracellular matrix synthesis and matrix metalloproteinase activity in renal epithelial cells and tumor cells. Controversial results have been published concerning the possible role of HGF in the pathogenesis of coronary atherosclerosis. In this study, we have investigated the effect of oxidized low density lipoproteins (LDL) and elevated glucose concentrations on HGF synthesis in cultured human coronary artery smooth muscle cells. In addition, we have studied whether HGF modulates the release of extracellular matrix, extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinases (MMP) by coronary artery smooth muscle cells. Oxidized LDL (1-10 microg/ml) induced a significant dose-dependent decrease of HGF release and a concomitant decrease of HGF mRNA expression, whereas native LDL and elevated glucose concentrations induced no significant changes of HGF synthesis. Incubation of cultured human coronary smooth muscle cells with human HGF (1-100 ng/ml) did not significantly alter cell migration and collagen I, fibronectin, EMMPRIN, MMP-1, MMP-2 and MMP-9 release. In summary, our results provide evidence that HGF does not promote coronary plaque growth or plaque destabilization. Regarding the fact that HGF is a potent endothelial cell regeneration factor, the observed downregulation of HGF synthesis by oxidized LDL supports the concept that HGF might be a protective factor in coronary atherosclerosis and that a decrease rather than an increase of HGF synthesis might promote coronary atherosclerosis.
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PMID:Oxidized LDL inhibit hepatocyte growth factor synthesis in coronary smooth muscle cells. 1609 93

Therapeutic strategies to prevent atherosclerotic plaque progression and achieve plaque stabilization involve 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitors (statins) and renin-angiotensin system (RAS)-blockade, but studies investigating the potentially additive effects of a combined treatment strategy are rare. We hypothesised that the adjunction of atorvastatin with telmisartan or ramipril might achieve additional effects on experimental atherosclerosis though statin-induced lipid-lowering is lacking. ApoE-/- mice were fed a high-fat diet for 12 weeks and randomized to either placebo (CON), atorvastatin (ATO), ramipril (RAM), telmisartan (TEL) or RAM+ATO and TEL+ATO (N=23 per group). RAS-blockade, but not ATO, reduced systolic blood pressure. None of the treatment regimens lowered systemic cholesterol levels or lipoprotein fractions. RAM, TEL and the combined therapy, but not ATO, significantly reduced aortic lipid deposition. All substances significantly reduced monocyte chemoattracting protein (MCP)-1 concentrations, macrophages and matrixmetalloproteinase (MMP)-9 content and enhanced plaque's content of tissue inhibitor of MMP (TIMP)-1, collagen and fibrous cap thickness, resulting in an overall decrease of advanced plaques (classified as types IV-VI). Additive effects of the adjunction were observed on MMP-9 gelatinolytic activity, interleukin (IL)-6 and IL-10 plasma levels. These results indicate that a combined treatment with RAS-blockade and statins may have additive effects on systemic cardiovascular risk markers even in the absence of lipid-reduction, although additional effects on atherosclerotic plaque progression and stability were not observed in this model.
Atherosclerosis 2005 Sep
PMID:Combined effects of HMG-CoA-reductase inhibition and renin-angiotensin system blockade on experimental atherosclerosis. 1611 75

Atherosclerotic plaque rupture is promoted by metalloproteinase (MMP)-2 and MMP-9, enzymes that degrade the fibrous cap leading to plaque erosion. MMP biosynthesis is mediated by prostaglandin (PG)E2, the product of cyclooxygenase (COX)-2/inducible PGE synthase (mPGES) activity. We have recently reported the overexpression of COX-2/mPGES-1 in vulnerable plaques as a basis of MMP-mediated plaque instability. Hypercholesterolemia and hypertension are two important risk factors for atherosclerosis. Recent trial showed that statins and AT1 receptor blockers significantly reduce the incidence of cardiovascular events in humans. Since anti-inflammatory effects have been reported in association to therapy with statins or AT1 receptor blockers, in two different studies we hypothesized that these drugs can stabilize atherosclerotic plaques through modulation of COX-2/mPGES-1-dependent MMP biosynthesis. Our data demonstrated the stabilizing effect of atherosclerotic plaques by simvastatin or irbesartan, that is due, at least in part, to the reduction of inflammatory burden and suppression of PGE2-dependent metalloproteinases release.
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PMID:Pharmacological modulation of plaque instability. 1621 85

Carotid atherosclerotic plaque remodelling and increased risk of symptomatic plaque rupture seem to be partially mediated by matrix metalloproteinases (MMPs). In this study, we have investigated whether different MMPs are related to carotid atherosclerosis or to recent ischaemic brain disease. Eighty-four consecutive patients undergoing carotid endarterectomy for symptomatic and asymptomatic disease were studied. Plaques were analysed by ultrasound and later by morphology. Plasma MMP-2, MMP-8 and MMP-9 levels were quantified by ELISA. MMP expression and activity in carotid plaques was analysed by Western blotting and in situ zymography. Results were analysed with respect to plaque stability, morphology, symptomatic disease, presence of vascular risk factors and plasma markers of acute inflammation as high sensitivity C-reactive protein (hsCRP), fibrinogen, D-dimer and white blood cell counts. Patients with hypoechogenic plaques on ultrasound had more plasma MMP-8 (p = 0.04) and increased MMP activity as assessed by in situ zymography. Asymptomatic patients with plaque progression had more active intraplaque MMP-8 than asymptomatic patients without plaque progression. Presence of recent intraplaque haemorrhage or past history of CAD was related to increased activity of MMPs as assessed by in situ zymography (p < 0.01, CI 95% 0.8-1.0). Plasma MMP-8 and MMP-9, but not MMP-2 levels, decrease with time after ischaemic stroke. Patients with hypertension had more intraplaque active MMP-9 than normotensive (p = 0.03, CI 95% 0.7-1.0). Hypoechogenic carotid plaques had increased MMP activity and asymptomatic patients with plaque progression show increase intraplaque MMP-8 levels.
Atherosclerosis 2006 Jul
PMID:Intraplaque MMP-8 levels are increased in asymptomatic patients with carotid plaque progression on ultrasound. 1625 88

This study investigated the expression of CD40, CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) in dietary-induced atherosclerosis in rats. Wister rats were fed with high cholesterol diet (As group, n = 6) or with normal diet (N group, n = 6). Blood cells that express CD40 and CD40L were sorted by flow cytometry, the MMP-2 and MMP-9 were measured by zymography method. The morphological locations of MMP-2 and MMP-9 in the aorta were studied with immunohistochemistry and by microscopy. The results showed that the expression of CD40, CD40L and matrix metalloproteinase were higher in As group than those in control group. The MMP-2 and MMP-9 were positive in As group but negative in control group by immunohistochemistry study. Our results suggest that the expression of CD40 and CD40L in the blood cells and the activities of MMP-2 and MMP-9 in plasma were higher in As group than those in Normal group, indicating that they may contribute to the formation of atherosclerosis.
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PMID:The expression of CD40-CD40L and activities of matrix metalloproteinases in atherosclerotic rats. 1631 21

Carotid intima-media thickness (IMT) and vascular inflammatory markers have been shown to be involved in atherosclerosis. This study was designed to investigate the effect of transdermal hormone replacement therapy (HRT) on carotid IMT and vascular inflammatory markers in postmenopausal women and to explore the interrelationship between the change in carotid IMT and the changes in vascular inflammatory markers. Thirty-five postmenopausal women (mean age 57.0+/-7.7 years) received transdermal HRT (continuous 17beta-estradiol patch [36 microg/day] plus cyclic oral medroxyprogesterone acetate [2.5 mg/day, for 12 days/ month]) for 12 months, and 32 controls (mean age 58.0+/-7.5 years) did not. Carotid IMT, assessed by ultrasound, and circulating vascular inflammatory markers, i.e., C-reactive protein (CRP), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, E-selectin, monocyte chemoattractant protein (MCP)-1, and matrix metalloproteinase (MMP)-9 were measured before and after 12 months of treatment. In the HRT group, carotid IMT decreased significantly (p<0.01), from 0.71+/-0.13 mm to 0.65+/-0.12 mm, and the ICAM-1, VCAM-1, E-selectin, and MCP-1 levels decreased significantly (p<0.01 for all), but the CRP and MMP-9 levels remained unchanged. Carotid IMT and vascular inflammatory markers were unchanged in the control group. In the HRT group, the change in carotid IMT was significantly correlated with the change in serum E-selectin (r=0.38, p<0.05), but not with the changes in other vascular inflammatory markers. These results suggest that transdermal HRT reduced carotid artery wall thickness, and that the reduction may have been induced by an antiatherosclerotic effect combined with the direct effect of estrogen and decreased levels of estrogen-induced E-selectin.
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PMID:Effect of transdermal hormone replacement therapy on carotid artery wall thickness and levels of vascular inflammatory markers in postmenopausal women. 1633 86


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