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)

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that directly control numerous genes of lipid metabolism by binding to response elements in the promoter. It has recently been proposed that PPARgamma may also regulate genes for proinflammatory proteins, not through PPRE binding but by interaction with transcription factors AP-1, STAT, and NF-kappaB. Recent studies with cultured human monocytes, however, have failed to observe an inhibitory effect of PPARgamma agonists on induced expression of TNFalpha and IL-6, genes known to be controlled by AP-1, STAT, and NF-kappaB. In a similar fashion, we show here that PPARalpha (fenofibrate) or PPARgamma (rosiglitazone) agonists failed to modulate LPS-induced secretion of IL-8 in THP-1 cells. When we made parallel observations on another gene, matrix metalloproteinase 9 (MMP-9), we were surprised to find profound downregulation of LPS-induced secretion by both PPARalpha or PPARgamma agonists. These findings suggest that PPAR may regulate only a subset of the proinflammatory genes controlled by AP-1, STAT, and NF-kappaB. Effects of PPARs on MMP-9 may account for the beneficial effect of PPAR agonists in animal models of atherosclerosis.
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PMID:Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells. 1062 22

In vascular tissues, chymase catalyzes the production of angiotensin II, which plays a crucial role in vascular diseases. Recent clinical studies and animal models of vascular proliferation and atherosclerosis have provided evidence that angiotensin II formed by chymase is involved in these processes. These observations suggest that chymase might promote the development of vascular proliferation and atherosclerosis. Chymase also activates matrix metalloproteinase 9, which promotes aortic aneurysm and angiogenesis, and thus chymase inhibitors might also prevent the progression of abdominal aortic aneurysm and angiogenesis. We propose that chymase is a novel target for preventing vascular diseases.
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PMID:Chymase as a novel target for the prevention of vascular diseases. 1538 Sep 35

Intima-media thickening (IMT) of carotid arteries and constrictive remodeling (CR) of atherosclerotic plaques are vascular pathologic characteristics that precede the onset of vascular events. SMC migration and proliferation are linked both to IMT and CR and are matrix metalloproteinase 9 (MMP-9) dependent. A genetic polymorphism (PM) of MMP-9, a CA (13-27) microsatellite in the promoter region, which accounts for differential expression of MMP-9, could be linked to progression of IMT and CR. Progression of IMT and CR of plaques in carotid arteries were studied in 55 consecutive patients with a 12-18 months follow-up. All patients were genotyped for MMP-9 PM. A positive linear relationship between the number of repeats and the progression of IMT (P=0.028) as well as of CR (P=0.018) was found. The analogous relationship was obtained when only the allele with longer microsatellite was considered. Carriers of more than 20 repeats in one allele showed faster both IMT growth (P=0.045) and stenosis progressions of plaques (P=0.019). In multivariate analysis, age, dyslipidemia, and MMP-9 PM were determinants of IMT progression, while MMP-9 PM was the only one of CR. In conclusion, the high number of CA repeats in MMP-9 promoter is positively correlated with faster IMT and CR progression.
Atherosclerosis 2005 Oct
PMID:MMP-9 microsatellite polymorphism: association with the progression of intima-media thickening and constrictive remodeling of carotid atherosclerotic plaques. 1615 1

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are expressed in smooth muscle cells (SMCs). This study was designed to compare the effects of PPARalpha and PPARgamma on SMC proliferation and migration and to determine how they operate. Treatment of SMCs from porcine coronary artery revealed that mitogen-stimulated DNA synthesis was blocked by the PPARalpha ligand 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643) and 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)) (a putative PPARgamma agonist) but not by the PPARgamma agonist rosiglitazone or the PPARbeta/delta ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy acetic acid (GW501516). Inhibition of DNA synthesis by clofibrate and 2-(4-(2-(1-cyclohexanebutyl-3-cyclohexylureido)ethyl)phenylthio)-2-methylproprionic acid (GW7647) confirmed that SMC proliferation is affected by PPARalpha. This conclusion was supported by the fact that WY14,643 also inhibited the proliferation of H4IIE hepatoma cells (expressing only PPARalpha) but not A10 SMCs (expressing only PPARgamma1). In contrast, the effective inhibition of all cell types with 15d-PGJ(2) indicated that this compound probably operates via a PPARgamma-independent mechanism. Interestingly, rosiglitazone did not inhibit DNA synthesis of either H4IIE or A10 cells, suggesting that the activation of PPARgamma does not influence cell proliferation. Phosphorylation of cyclin-dependent kinase 2 and expression of proliferating cell nuclear antigen were inhibited by WY14,643 but not by rosiglitazone or 15d-PGJ(2), indicating that PPARalpha prevents progression into S phase. Although rosiglitazone did not block SMC proliferation, it (like WY14,643) reduced neointimal hyperplasia in vitro. This observation can be rationalized by the fact that both WY14,643 and rosiglitazone inhibit SMC migration, probably through matrix metalloproteinase 9. Our study therefore shows that selective interference with mediators of cell cycle progression and cell migration via activation of PPARs may prevent growth-related vascular diseases such as restenosis and atherosclerosis.
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PMID:Peroxisome proliferator-activated receptor alpha and gamma ligands differentially affect smooth muscle cell proliferation and migration. 1640 62

Human matrix metalloproteinase 9 (MMP-9), also called gelatinase B, is particularly involved in inflammatory processes, bone remodelling and wound healing, but is also implicated in pathological processes such as rheumatoid arthritis, atherosclerosis, tumour growth, and metastasis. We have prepared the inactive E402Q mutant of the truncated catalytic domain of human MMP-9 and co-crystallized it with active site-directed synthetic inhibitors of different binding types. Here, we present the X-ray structures of five MMP-9 complexes with gelatinase-specific, tight binding inhibitors: a phosphinic acid (AM-409), a pyrimidine-2,4,6-trione (RO-206-0222), two carboxylate (An-1 and MJ-24), and a trifluoromethyl hydroxamic acid inhibitor (MS-560). These compounds bind by making a compromise between optimal coordination of the catalytic zinc, favourable hydrogen bond formation in the active-site cleft, and accommodation of their large hydrophobic P1' groups in the slightly flexible S1' cavity, which exhibits distinct rotational conformations of the Pro421 carbonyl group in each complex. In all these structures, the side-chain of Arg424 located at the bottom of the S1' cavity is not defined in the electron density beyond C(gamma), indicating its mobility. However, we suggest that the mobile Arg424 side-chain partially blocks the S1' cavity, which might explain the weaker binding of most inhibitors with a long P1' side-chain for MMP-9 compared with the closely related MMP-2 (gelatinase A), which exhibits a short threonine side-chain at the equivalent position. These novel structural details should facilitate the design of more selective MMP-9 inhibitors.
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PMID:Crystal structures of MMP-9 complexes with five inhibitors: contribution of the flexible Arg424 side-chain to selectivity. 1759 56

Recent investigations of atherosclerosis have focused on inflammation, providing new insight into mechanisms of disease. Inflammatory cytokines involved in vascular inflammation stimulate the generation of endothelial adhesion molecules, proteases, and other mediators, which may enter the circulation in soluble form. These primary cytokines also induce production of the messenger cytokine interleukin-6, which stimulates the liver to increase production of acute-phase reactants such as C-reactive protein. In addition, platelets and adipose tissue can generate inflammatory mediators relevant to atherothrombosis. Despite the irreplaceable utility of plasma lipid profiles in assessment of atherosclerotic risk, these profiles provide an incomplete picture. Indeed, many cardiovascular events occur in individuals with plasma cholesterol concentrations below the National Cholesterol Education Program thresholds of 200 mg/dL for total cholesterol and 130 mg/dL for low-density lipoprotein (LDL) cholesterol. The concept of the involvement of inflammation in atherosclerosis has spurred the discovery and adoption of inflammatory biomarkers for cardiovascular risk prediction. C-reactive protein is currently the best validated inflammatory biomarker; in addition, soluble CD40 ligand, adiponectin, interleukin 18, and matrix metalloproteinase 9 may provide additional information for cardiovascular risk stratification and prediction. This review retraces the biology of atherothrombosis and the evidence supporting the role of inflammatory biomarkers in predicting primary cardiovascular events in this biologic context.
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PMID:Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. 1816 Jul 25

Type 2 diabetes mellitus is associated with elevated plasma triglyceride levels, low high-density lipoprotein cholesterol, and a high incidence of cardiovascular disease. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and fibrates are frequently used in the treatment of diabetic dyslipidemia, but their specific impact on the inflammation processes involved in atherosclerosis remains to be fully characterized. The objective of this 2-group parallel study was to investigate the differential effects of a 6-week treatment with either atorvastatin 20 mg/d alone (n = 19) or micronized fenofibrate 200 mg/d alone (n = 19) on inflammation, cell adhesion, and oxidation markers in type 2 diabetes mellitus subjects with marked hypertriglyceridemia. In addition to the expected changes in lipid levels, atorvastatin decreased plasma levels of C-reactive protein (-26.9%, P = .004), soluble intercellular adhesion molecule 1 (-5.4%, P = .03), soluble vascular cell adhesion molecule 1 (-4.4%, P = .008), sE-selectin (-5.7%, P = .02), matrix metalloproteinase 9 (-39.6%, P = .04), secretory phospholipase A(2) (sPLA(2)) (-14.8%, P = .04), and oxidized low-density lipoprotein (-38.4%, P < .0001). On the other hand, fenofibrate had no significant effect on C-reactive protein levels and was associated with reduced plasma levels of sE-selectin only (-6.0%, P = .04) and increased plasma levels of sPLA(2) (+22.5%, P = .004). These results suggest that atorvastatin was potent to reduce inflammation, oxidation, and monocyte adhesion in type 2 diabetes mellitus subjects with marked hypertriglyceridemia, whereas fenofibrate decreased sE-selectin levels only and was associated with an elevation of sPLA(2) levels.
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PMID:Differential effect of atorvastatin and fenofibrate on plasma oxidized low-density lipoprotein, inflammation markers, and cell adhesion molecules in patients with type 2 diabetes mellitus. 1824 11

Increasing evidence indicated that plaque stabilization is attributed to the composition of the atherosclerotic plaque, and inflammation plays an important role in the formation and progress of vulnerable atherosclerotic plaque (VAP), which is prone to rupture. Emodin, an important component of traditional Chinese herb rhubarb, has obvious anti-inflammatory effect, although its effect on atherosclerotic plaque stabilization is unknown. Apolipoprotein E (ApoE) is an important component of plasma lipoprotein with anti-atherosclerosis function, and the plaque in the aorta of ApoE-deficient mice has been demonstrated with characteristics of VAP. Therefore, this study was designed to determine whether emodin can stabilize the VAP in the ApoE-deficient mice and explain the possible mechanism. After fat-fed for 13 weeks, mice were randomized into three groups (11 animals/group) and intragastrically administrated with emodin, simvastatin or distilled water for 13 weeks, respectively. The plaque stability was evaluated by the morphology and composition of atherosclerotic plaques. Additionally, the expression of peroxisomal proliferator-activated receptor-gamma (PPAR-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase 9 (MMP-9) in plaques was determined by the immunohistochemistry method. We showed that emodin could decrease the lipid core area and the ratio of lipid to collagen content in plaques. In addition, emodin significantly inhibited the expression of GM-CSF and MMP-9, whereas it induced the expression of PPAR-gamma in plaques. In conclusion, these results suggest that emodin can stabilize the VAP in the aortic root of ApoE-knockout mice, which is probably due to its anti-inflammatory effect.
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PMID:Emodin promotes atherosclerotic plaque stability in fat-fed apolipoprotein E-deficient mice. 1850 36

Imaging of enzyme activity is a central goal of molecular imaging. With the introduction of fluorescent smart probes, optical imaging has become the modality of choice for experimental in vivo detection of enzyme activity. Here, we present a novel high-relaxivity nanosensor that is suitable for in vivo imaging of protease activity by magnetic resonance imaging. Upon specific protease cleavage, the nanoparticles rapidly switch from a stable low-relaxivity stealth state to become adhesive, aggregating high-relaxivity particles. To demonstrate the principle, we chose a cleavage motif of matrix metalloproteinase 9 (MMP-9), an enzyme important in inflammation, atherosclerosis, tumor progression, and many other diseases with alterations of the extracellular matrix. On the basis of clinically tested very small iron oxide particles (VSOP), the MMP-9-activatable protease-specific iron oxide particles (PSOP) have a hydrodynamic diameter of only 25 nm. PSOP are rapidly activated, resulting in aggregation and increased T2*-relaxivity.
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PMID:Protease-specific nanosensors for magnetic resonance imaging. 1900 61

Total panax notoginsenosides (TPNS) are the main active ingredients in San-Chi, the root of Panax notoginseng (Burk) F.H. Chen, which belongs to the Araliaceae family and has been used in traditional Chinese medicine to treat atherosclerosis. We investigated the effect of TPNS on serum lipid levels and cell differentiation antigen 40 (CD40) and matrix metalloproteinase 9 (MMP-9) expression in atherosclerosis in apolipoprotein E-knockout (apoE-KO) mice fed a high-fat, high-cholesterol diet. Twenty-four apoE-KO mice were divided into two groups, the ApoE-KO group and the ApoE-KO + TPNS group. TPNS (60 mg/kg) was orally administered daily for 12 weeks in ApoE-KO + TPNS group. After 12 weeks, blood and aortas were obtained. Serum levels of lipid were analyzed, serum oxidized low density lipoprotein (oxLDL) concentration, ratio of plaque area-to-vessel area and the expression of CD40 and MMP-9 were examined by ELISA, histological staining, immunohistochemistry and real-time PCR, respectively. It was observed in our study that serum levels of lipid and oxLDL, ratio of plaque area to vessel area, and expression of CD40 and MMP-9 were lower in the ApoE-KO + TPNS group than in the ApoE-KO group. These results suggest that TPNS could prevent atherosclerosis by lowering serum lipid levels and regulating vascular CD40 and MMP-9 expression. TPNS may have implications for clinical treatment of atherosclerosis vascular disease.
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PMID:Total panax notoginsenosides prevent atherosclerosis in apolipoprotein E-knockout mice: Role of downregulation of CD40 and MMP-9 expression. 1970 33


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