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)

Clinical complications of atherosclerosis are often triggered by the rupture of unstable plaques, while thinning of the atherosclerotic vessel wall owing to elastin and collagen degradation and media necrosis may result in aneurysm formation and bleeding. Proteolysis, mediated via the plasminogen/plasmin and/or matrix metalloproteinase (MMP) systems may contribute to neovascularization and rupture of plaques, or to ulceration and rupture of aneurysms. In an in vivo model of atherosclerosis, using mice that had a combined deficiency of apolipoprotein E (ApoE) and urokinase-type plasminogen activator (u-PA) and that were maintained on a cholesterol-rich diet, it was observed that u-PA deficiency protects against aneurysm formation. This was explained by the findings that plasmin, generated from plasminogen by u-PA, activates several macrophage-secreted proMMPs (e.g. proMMP-3, -9, -12 and -13), which in turn cause extracellular matrix degradation. A potential role for MMP-3 (stromelysin-1) was confirmed in a subsequent study using mice with a combined deficiency of ApoE and MMP-3, that were kept on a cholesterol-rich diet. The results suggest that MMP-3 contributes to plaque destabilization, possibly by degrading extracellular matrix components, but also promotes aneurysm formation by degrading the elastic lamina. These effects may be mediated by MMP-3 directly or by activation of other proMMPs or other (proteolytic) systems. A functional role of MMPs is further supported by the finding that deficiency in TIMP-1 (tissue inhibitor of MMPs type 1) reduces atherosclerotic plaque size but enhances aneurysm formation. Taken together, these results suggest that u-PA has an important role in the structural integrity of the atherosclerotic vessel wall, which is likely to involve triggering the activation of MMPs and, furthermore, they suggest that increased u-PA levels are a risk factor for aneurysm formation.
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PMID:Extracellular proteolysis in the development and progression of atherosclerosis. 1202 44

Platelet-derived growth factor (PDGF) stimulates expression of matrix metalloproteinases (MMPs), including stromelysin-1 (MMP-3). Induction of these expressions is known to occur during the course of atherosclerosis, tumor invasion, and metastasis. We investigated PDGF-alpha receptor (alphaR)- and beta receptor (betaR)-mediated signaling pathways for the expression of MMP-3 and invasion activity using porcine aortic endothelial (PAE) cells with stable expression of normal or mutated PDGF receptors. RT-PCR and Western blot analyses revealed that PDGF-BB induces MMP-3 expression in PAE cells that exclusively express either the PDGF-alphaR or the -betaR, but not in non-transfected control cells. To identify the signals necessary for PDGF receptor-mediated induction of MMP-3 expression, several lines of PAE cells expressing mutant PDGF receptors were further analyzed. Cells expressing mutant PDGF receptors unable to associate with Src or PLCgamma, retained the ability to induce MMP-3 expression as a result of PDGF-BB stimulation. However, incubation with PDGF-BB did not induce MMP-3 expression in cells expressing a mutant PDGF-betaR unable to associate with phosphatidylinositol 3(')-kinase (PI3K). LY294002, a PI3K inhibitor, reduced PDGF-BB-stimulated MMP-3 expression in PAE cells expressing wild-type PDGF receptors. In contrast, PDGF-BB induced MMP-3 expression in the presence of U-73122, a PLCgamma inhibitor. Moreover, PDGF-BB enhanced the invasiveness of cells expressing wild type PDGF-beta receptors, but not of cells expressing mutant PDGF-betaRs impaired in their ability to associate with PI3K. In light of these results, it appears that PDGF-BB is capable of inducing MMP-3 expression through both the PDGF-alphaR and the -betaR, and the effects are contributed by the PI3K-mediated transduction pathways.
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PMID:Functional analysis of aortic endothelial cells expressing mutant PDGF receptors with respect to expression of matrix metalloproteinase-3. 1205 99

Coronary artery disease is among the leading causes of death worldwide. Clinical trials show a protective effect of statins against the sequelae of coronary artery disease. The mean risk reductions for subjects using statins compared with placebo found in these trials is about 30%. These are average reductions for all patients included in the trials. Important factors in interpreting the variability in the outcome of drug therapy include the patient's health profile, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. This review aims to give an overview of the known polymorphisms (Cholesteryl Ester Transfer Protein polymorphism, Stromelysin-1 polymorphism, -455G/A and TaqI polymorphisms of the beta-fibrinogen gene, apoE4, Asp(9)Asn mutation in the lipoprotein lipase gene, the -514 CT polymorphism in the hepatic lipase gene and the ACE deletion type gene) that have an influence on the effects of statins in the general population. The expectation is that in the future a subject's genotype may determine whether he will be treated with statins or not. Determining the genotype will not deny therapy to a subject, but will help in deciding the therapy that will suit the patient best.
Atherosclerosis 2002 Aug
PMID:Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors. 1205 67

Matrix metalloproteinases contribute to vascular remodeling by breaking down extracellular-matrix while new matrix is synthesized. Of the variety of MMPs, stromelysin-1 and gelatinase B may have key roles in coronary artery atherosclerosis. Moreover, The 5A/6A polymorphism in the promoter region of the stromelysin-1 gene may be a pathogenetic risk factor for acute myocardial infarction. Gelatinase B (92-kDa type IV collagenase and MMP-9) is one of the MMPs found to be highly expressed in the disruption-prone regions of atherosclerotic plaques. C- to T substitution at the promoter site (-1562) resulted in the higher promoter activity of the T-allelic promoter. The R279Q polymorphism in exon 6 led to the substitution of adenosine by guanine, and was a common polymorphism in the general population. We evaluated the relation between these polymorphisms and stable angina, the severity of atherosclerosis in coronary artery disease, and in-stent restenosis after percutaneous coronary angioplasty. The study population was composed of 131 patients with stable angina (mean age 61.3 years, 89 males) and 117 control subjects (mean age 59.3 years, 59 males). Coronary angiographies were performed in all cases at Yonsei University Cardiovascular Hospital from February 1998 to June 2000. The genotype for each polymorphism was determined using a SNaPshotTM kit and by restriction fragment length polymorphism (RFLP). The prevalence of 5A containing a polymorphism of the stromelysin-1 gene was higher in the stable angina group than in control patients, but no difference in the two polymorphisms of the gelatinase B gene was found between the two groups. By multiple logistic analysis, the 5A-allele of the stromelysin-1 gene was found to be an independent risk factor of stable angina with an odds ratio of 2.29 (95% CI; 1.19-4.38). However, the severity of atherosclerosis in coronary artery or in stent restenosis was not related to any polymorphism of stromelysin-1 or gelatinase B. Our results show that functional genetic variation of stromelysin-1 could be a significant risk factor for stable angina, and might play an important role in coronary atherosclerosis involving vascular remodeling.
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PMID:The roles of stromelysin-1 and the gelatinase B gene polymorphism in stable angina. 1220 36

Diabetes is a major risk factor for atherosclerosis. Hyperglycemia is an underlying contributing factor; however, the mechanisms that mediate the vascular complications are not yet fully understood. In the present study, we provide evidence that elevated glucose induces discordant matrix metalloproteinase (MMP) expression from two key vascular cells, endothelial cells and macrophages. Our results clearly indicate that high glucose (25 mM) induced endothelial cell expression and activity of the collagenase, MMP-1 and the gelatinase, MMP-2, whilst reducing expression of the stromelysin, MMP-3 (P<0.05). Similarly, our results show that high glucose (25 mM) induces expression and activity of MMP-9 from monocyte-derived macrophages (P<0.05). High glucose culture did not affect metalloproteinase inhibitor (TIMP-1) expression. Our results suggest for the first time that high glucose exposure induced discordant regulation of the MMP/TIMP system in vascular cells. The increased MMP-1, MMP-2 and MMP-9 activities induced by high glucose exposure could promote matrix degradation thereby accelerating atherogenesis and potentially reducing plaque stability in diabetes.
Atherosclerosis 2003 Jun
PMID:High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes. 1280 9

Atherosclerosis has been linked to Chlamydia pneumoniae infection. In atherosclerotic arteries chlamydiae infect macrophages, endothelial cells, and smooth muscle cells (SMC). It has been suggested that the proteolysis of the extracellular matrix by matrix metalloproteinases (MMPs) is involved in the destabilisation and rupture of atherosclerotic plaques. In this study we investigated the expression of several MMPs and tissue inhibitors of MMP (TIMPs) in C. pneumoniae-infected SMC using reverse transcription-polymerase chain reaction analysis. Chlamydial infection of SMC up-regulated the mRNA levels of MMP-1 (interstitial collagenase) and MMP-3 (stromelysin) but did not affect the expression of MMP-2 and -9 (gelatinases). Additionally, the levels of TIMP-1 and -2 mRNA remained unchanged upon infection. Cells infected with C. pneumoniae secreted increased quantities of MMP-1 and -3 proteins as demonstrated by enzyme-linked immunosorbent assays. The ability of C. pneumoniae to stimulate the production of MMP-1 and -3 by SMC may be important for its pathogenic role in the progression of atherosclerotic disease.
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PMID:Increased production of matrix metalloproteinases 1 and 3 by smooth muscle cells upon infection with Chlamydia pneumoniae. 1312 50

Basic fibroblast growth factor (FGF-2) and matrix metalloproteinases (MMPs) play key roles in vascular remodeling. Because FGF-2 controls a number of proteolytic activities in various cell types, we tested its effect on vascular endothelial cell expression of MMP-3 (stromelysin-1), a broad-spectrum proteinase implicated in coronary atherosclerosis. Endothelial cells (EC) from FGF-2-/- mice are highly responsive to exogenous FGF-2 and were therefore used for this study. The results showed that treatment of microvascular EC with human recombinant FGF-2 results in strong induction of MMP-3 mRNA and protein expression. Upregulation of MMP-3 mRNA by FGF-2 requires de novo protein synthesis and activation of the ERK-1/2 pathway. FGF-2 concentrations (5-10 ng/ml) that induce rapid and prolonged (24 h) activation of ERK-1/2 upregulate MMP-3 expression. In contrast, lower concentrations (1-2 ng/ml) that induce robust but transient (<8 h) ERK-1/2 activation are ineffective. Inhibition of ERK-1/2 activation at different times (-0.5 h to +8 h) of EC treatment with effective FGF-2 concentrations blocks MMP-3 upregulation. Thus, FGF-2 induces EC expression of MMP-3 with a threshold dose effect that requires sustained activation of the ERK-1/2 pathway. Because FGF-2 controls other EC functions with a linear dose effect, these features indicate a unique role of MMP-3 in vascular remodeling.
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PMID:Induction of stromelysin-1 (MMP-3) by fibroblast growth factor-2 (FGF-2) in FGF-2-/- microvascular endothelial cells requires prolonged activation of extracellular signal-regulated kinases-1 and -2 (ERK-1/2). 1462 61

The effect of genistein on aortic atherosclerosis was studied by immunohistochemistry with RAM-11 and HHF-35 antibodies and western blotting for matrix metalloproteinase-3 (MMP-3) in New Zealand White rabbits. After provocation of atherosclerosis with hyperlipidemic diet, the rabbits were divided as hyperlipidemic diet group (HD), normal diet group (ND) and hyperlipidemic plus genistein diet group (HD+genistein) for 4 and half months. The average cross sectional area of atherosclerotic lesion was 0.269 mm2 after provocation. The lesion was progressed by continuous hyperlipidemic diet (10.06 mm2) but was increased mildly by genistein (0.997 mm2), and decreased by normal diet (0.228 mm2). The ratio of macrophages to smooth muscle cells in the lesion was not changed by genistein supplementation. The western blotting showed reduction of MMP-3 expression in HD+genistein and ND groups than HD group. The inhibition of atherogenesis by genistein was might be due to improve the endothelial dysfunction rather than direct action on macrophages and/or smooth muscle cells in the lesion, since endothelial dysfunction by lipid peroxidation was the main atherogenic factor in the hypercholesterolemic rabbits. The genistein supplementation also suggests that it helps the stabilization of the atherosclerotic lesion by inhibition of MMP-3 expression.
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PMID:Genistein supplementation inhibits atherosclerosis with stabilization of the lesions in hypercholesterolemic rabbits. 1548 39

Atherosclerosis is still an important disease. It accounts for 39% of deaths in the U.K. and 12 million U.S citizens have atherosclerosis-associated disease. Atherosclerosis may exert clinical effects by slow narrowing, producing stable angina or dramatic rupture, producing acute coronary syndromes such as unstable angina or myocardial infarction and death. Macrophages are abundant in ruptured atherosclerotic plaques. Macrophages are innate immune effectors, i.e. they are activated without antigenic specificity. This may make them liable to indiscriminate tissue damage, since they are less selective than lymphocytes. Macrophages are recruited and activated by many signals and have an impressive armamentarium of molecules to promote tissue damage. Macrophage recruitment by abnormal endothelium over developing atherosclerotic plaques, is aided by endothelial expression of adhesion molecules (ICAM-1, VCAM, ELAM). Use of knockout mice has implicated the chemoattractant cytokine (chemokine) MCP-1 in attracting macrophage recruitment in atherosclerosis. Macrophage-activation stimuli associated with atherosclerotic risk factors include oxidised low density lipoprotein (oxLDL, "bad cholesterol"), advanced glycosylation end products (AGEs) of diabetes, angiotensin II and endothelin. Substantial work has clarified macrophage activation by OxLDL via macrophage scavenger receptors (MSRs), especially MSRA and CD36. Activated macrophages express effector molecules that kill cells and degrade extracellular matrix. These include Fas-L and nitric oxide (NO). Macrophage NO is derived from the high output inducible nitric oxide synthase (iNOS) pathway and upregulates vascular smooth muscle (VSMC) cell surface Fas, priming them for apoptosis. Activated macrophages express surface Fas-L, similar to cytotoxic T-lymphocytes and natural killer cells. Since VSMCs promote plaque stability, VSMC apoptosis may promote plaque rupture. Macrophages express multiple metalloproteinases (e.g. stromelysin) and serine proteases (e.g. urokinase) that degrade the extracellular matrix, weakening the plaque and making it rupture prone. Macrophages secrete numerous other effectors including reactive oxygen species, eicosanoids, tumour necrosis factor alpha and interleukin-1. Macrophage-derived transforming growth factor beta promotes fibrosis. Existing cardiovascular treatments including angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, aspirin, cholesterol reduction agents especially statins may inhibit macrophages. The interaction of NO-donors with macrophages and apoptosis is complex and bifunctional. Traditional anti-inflammatory agents such as glucocorticoids and cyclophosphamide have very serious side effects and are probably inappropriate. Novel anti-inflammatory agents e.g. new immunosuppressives and anti-TNF therapy may have an improved cost-benefit ratio.
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PMID:Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. 1563 83

Hypertriglyceridemia is an important risk factor for atherosclerosis, especially in obesity. Macrophages are one of the primary cell types involved in atherogenesis and are thought to contribute to lesion formation through both lipid accumulation and proinflammatory gene expression. In this study, we sought to determine the direct impact of triglyceride (TG)-rich VLDL-induced lipid accumulation on macrophage proinflammatory processes. Incubation of mouse peritoneal macrophages with 100 microg/ml VLDL for 6 h led to 2.8- and 3.7-fold increases in intracellular TGs and FFAs, respectively (P < 0.05). The inflammatory proteins tumor necrosis factor-alpha, interleukin-1beta, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein-1alpha (MIP-1alpha) were all upregulated by at least 2-fold (P < 0.05) in a dose-dependent manner in VLDL-treated macrophages. The increase in inflammatory gene expression coincided with the phosphorylation of the mitogen-activated protein kinase (MAPK) pathway members extracellular signal-regulated kinase (ERK) 1/2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38 MAPK and was ameliorated by U0126, an inhibitor of ERK1/2. Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1alpha gene expression. These data indicate that VLDL hydrolysis, and the subsequent accumulation of intracellular FFAs and TGs, plays a substantive role in mediating the proinflammatory effects of VLDL. These data have important implications for the direct proatherogenic effects of VLDL on macrophage-driven atherosclerosis.
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PMID:The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages. 1663 77


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