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)

The roles of transforming growth factor (TGF)-beta 1 in vascular proliferation, atherosclerosis, and plaque still remain controversial. TGF-beta 1 has been previously reported to inhibit the proliferation and migration of vascular smooth muscle cells and endothelial cells, in vitro. On the other hand, administration or transgenic overexpression of TGF-beta 1 enhances extracellular matrix synthesis and cellular hyperplasia of the intima and media in the normal artery and injured artery in vivo. We evaluated the correlation of arterial proliferation with plasma levels of TGF-beta 1 and TGF-beta receptor type II, respectively, in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new strain of spontaneous non-insulin-dependent diabetes mellitus (NIDDM) models. OLETF rats (n=30) were divided into three groups aged 5,15, and 30 weeks. Long-Evans Tokushima Otsuka (LETO) rats (n=30) were used as age-matched non-diabetic controls. Plasma TGF-beta1 and insulin were determined by enzyme-linked immunosorbent assay. Immunoreactive TGF-beta receptor type II antigen was detected by immunohistochemistry on the thoracic artery. Arterial media area was measured microscopically. Oral glucose tolerance test was performed to examine the stage of diabetes mellitus. The thoracic aorta wall section area increased significantly from the age of 15 weeks in OLETF rats, versus LETO rats. In both OLETF and LETO rats, plasma TGF-beta 1 increased significantly from the age of 15 weeks. In OLETF rats, plasma TGF-beta 1 increased significantly over that in LETO rats (P<0.001). Furthermore, TGF-beta receptor type II was detected on aortic wall as strong signals in OLETF rats, but only weakly in LETO rats. OLETF rats showed hyperinsulinemia and insulin resistance from the age of 15 weeks. With oral glucose tolerance test, from the age of 15 weeks, the high glucose level in OLETF rats was prolonged to 2 h after loading, and the insulin levels at both fasting and after loading were significantly higher than those of LETO rats (P<0.001). There are significant linear relations between plasma TGF-beta 1 antigen and aorta wall section area, and plasma TGF-beta 1 antigen and fasting insulin level (P<0.001, respectively). We found that plasma TGF-beta 1 and vascular TGF-beta type II receptors existed to a greater extent in pre- and early stages of diabetes mellitus (DM) in OLETF rats compared with LETO rats. The greater extent of each in OLETF rats was associated with hyperinsulinemia and/or vascular thickening.
Atherosclerosis 2002 May
PMID:Vascular proliferation and transforming growth factor-beta expression in pre- and early stage of diabetes mellitus in Otsuka Long-Evans Tokushima fatty rats. 1194 99

The aim of this study was to determine, if gemfibrozil has anti-atherogenic actions on human vascular smooth muscle cells (SMCs) and whether these actions are affected by high glucose concentrations, which mimic the hyperglycemia of diabetes. Proliferation of SMCs treated with gemfibrozil was estimated by cell counting (Coulter Counter) and [3H]thymidine incorporation, migration in a scrape-wound assay, proteoglycan (PG) biosynthesis and glycosaminoglycan (GAG) synthesis on xyloside by [35S]sulfate labeling and sizing by sodium dodecyl sulphide-polyacrylamide gel electrophoresis (SDS-PAGE). Gemfibrozil (100 micromol/l) did not affect migration in low or high glucose media. Gemfibrozil caused concentration-dependent inhibition of proliferation in low glucose media (24% inhibition at 100 micromol/l, P<0.01) and inhibited the re-initiation of DNA synthesis by 33.3% (100 micromol/l, P<0.05) in low glucose and 31.4% (100 micromol/l, P<0.001) in high glucose conditions. In low and high glucose media, gemfibrozil (100 micromol/l) reduced total PG production in the presence of TGF-beta 1, which was associated with a decrease in the apparent size of PGs. Gemfibrozil and another PPAR-alpha ligand, WY-14643, significantly inhibited basal and TGF-beta1 stimulated GAG synthesis. We conclude that some SMCs properties associated with atherogenesis are favorably affected by gemfibrozil. Hence, direct vascular actions of gemfibrozil observed in this study may contribute to the reduction in cardiovascular disease observed in clinical studies with gemfibrozil.
Atherosclerosis 2002 May
PMID:Differential effects of gemfibrozil on migration, proliferation and proteoglycan production in human vascular smooth muscle cells. 1194 5

The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-beta, and a pivotal role for TGF-beta in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-beta inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-beta receptor II (TGFbetaRII:Fc), which inhibits TGF-beta signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 microg, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-beta signaling treatment resulted in a prominent increase in CD3- and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGFbetaRII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGFbetaRII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-beta in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.
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PMID:Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. 1206 7

Inflammatory markers have been demonstrated to be associated with increased risk of cardiovascular events. In this setting, C-reactive protein (CRP) was shown to add predictive value to cholesterol levels. We investigated hypercholesterolemic patients and related their inflammatory variables and their coagulation state focusing on factor VII, a coagulation protein which plays an established role in thrombogenesis. We examined the relationship between factor VII clotting activity (FVIIc), FVII antigen (FVIIAg) and activated FVII (FVIIa) levels against CRP, interleukin-6 soluble receptor (IL-6sR), P-selectin, soluble intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-beta(1) (TGF-beta(1)), in fifty-eight hypercholesterolemic subjects. Patients were subjected to 6-8 weeks of lipid lowering treatment with diet or diet plus pravastatin (40 mg/day). Univariate analysis showed that FVII levels were positively associated with CRP (FVIIAg: r=0.56, P<0.0001; FVIIc: r=0.57, P<0.0001; FVIIa: r=0.39, P<0.001) and IL-6sR (FVIIAg: r=0.59, P<0.0001; FVIIc: r=0.52, P<0.0001; FVIIa: r=0.47; P<0.001). CRP was still correlated, at the baseline, with FVIIAg and FVIIc levels after multiple stepwise regression analysis (FVIIAg: P<0.0001; FVIIc: P<0.0001, respectively) and with FVIIAg at the end of lipid lowering treatment (P<0.0001). Our data indicate that the FVII level is independently associated with inflammatory variables and suggest their pathophysiological link in hypercholesterolemic patients.
Atherosclerosis 2002 Nov
PMID:Association of factor VII levels with inflammatory parameters in hypercholesterolemic patients. 1220 82

Plasminogen activator inhibitor type 1 (PAI-1), a risk marker of atherosclerosis, is highly expressed in adipose tissue from obese subjects. PAI-1 is also considered as an acute phase protein. Recently, adipose tissue has been described as a source of inflammatory cytokines. Therefore, our aim was to study the relationships between PAI-1, and IL-6, TNF, TNF receptors (TNFRSF1s) and TGFbeta1, in plasma and adipose tissue from obese (n = 60) and lean (n = 28) subjects. Study has been extended to plasminogen activators (t-PA and u-PA). Compared to lean subjects, obese subjects exhibited higher plasma levels of all the studied parameters (except for TGFbeta1) whereas in adipose tissue only PAI-1, t-PA and TGFbeta antigen levels differed. In the obese population, plasma PAI-1 levels were weakly associated with circulating TNF, and this relationship disappeared after adjustment for plasma t-PA. Adipose tissue PAI-1 levels were positively associated with TNFRSF1s and TGFbeta, the strongest relationship being observed with TNFRSF1A, which explained 82% of PAI-1 variability. TNF and IL-6 were the main contributors to t-PA variability in plasma and in adipose tissue, respectively. Our results argue on the relevance of TNFRSF1s in the regulation of PAI-1 expression by adipose tissue. Association between t-PA, which is mainly produced by endothelial cells, and IL-6 or TNF suggest that inflammation might be involved in angiogenesis in adipose tissue.
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PMID:Relationships between fibrinolytic and inflammatory parameters in human adipose tissue: strong contribution of TNFalpha receptors to PAI-1 levels. 1235 79

Connective tissue growth factor (CTGF) has recently received much attention as a possible key determinant of progressive fibrosis and excessive scarring and also of wound repair, neoangiogenesis, bone formation and embryonic development. CTGF is also up regulated in numerous fibrotic diseases, including atherosclerosis and lung-, skin-, pancreas-, liver- and kidney-fibrosis. TGFbeta induces CTGF through different signaling pathways and a specific TGFbeta responsive element in the CTGF promoter. CTGF is thought to act both as a profibrotic marker and as a downstream effector of TGFbeta by mediating at least some of its profibrotic activities. CTGF is an interesting target for future antifibrotic therapies as it is conceivable that inhibition of CTGF might block the profibrotic effects of TGFbeta, without affecting TGFbeta's anti-proliferative and immunosuppressive effects. In addition to TGFbeta, a number of other regulators of CTGF expression have been identified, including vascular endothelial growth factor, tumor necrosis factor alpha, shear stress, cell stretch and static pressure, H(2)O(2), O(2) and NO. In addition to trans-regulatory mechanisms, specific transcription factor binding sites in the CTGF promoter, as well as 3'untranslated region (UTR) regulatory sequences have been identified that are important for basal and induced CTGF expression. Outlining the mechanisms that underlie CTGF gene regulation in normal and fibrotic cells, might help design of future intervention strategies aiming at targeted specific interference with CTGF expression at sites of progressive fibrosis. In addition, alternative therapies targeting CTGF effects are proposed which might lead to a favorable outcome of wound repair and fibrosis.
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PMID:Gene regulation of connective tissue growth factor: new targets for antifibrotic therapy? 1239 58

Albumin modified by Amadori glucose adducts has been shown to modulate signal transduction and induce alterations in renal glomerular cells that contribute to the development of diabetic nephropathy. However, the participation of this nonenzymatically glycated protein in the pathobiology of atherosclerotic cardiovascular disease in diabetes has not been established. To probe this issue, we used macrophage RAW cells to assess the effects of glycated albumin on molecular events implicated in the pathogenesis of diabetes-related vascular complications. RAW cells were cultured in medium containing 5.5 mmol/L glucose and glycated or nonglycated albumin, with and without the addition of PD98059, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK), followed by analysis of phosphorylated ERK and the nuclear translocation of nuclear factor (NF)-kappa B and measurement of cellular content of thiobarbituric acid-reactive substances and the concentration of transforming growth factor (TGF)-beta(1) in the spent medium. We demonstrate, for the first time, that glycated albumin activates RAW cell ERK and promotes ERK-dependent increases in TGF-beta(1) production, oxidative stress, and NF-kappa B activation. Preincubation with the antioxidant alpha-lipoic acid partially prevented the glycated albumin-induced increase in NF-kappa B activation. These findings indicate that Amadori-modified glycated albumin modulates macrophage cell biology independent of high glucose concentration. The effects of glycated albumin on RAW cell molecular mediators and cytokine production may have pathophysiologic significance with respect to the accelerated atherosclerosis that occurs in diabetes.
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PMID:Glycated albumin increases oxidative stress, activates NF-kappa B and extracellular signal-regulated kinase (ERK), and stimulates ERK-dependent transforming growth factor-beta 1 production in macrophage RAW cells. 1267 69

Restenosis is responsible to approximately 30% of long-term failure following therapeutic vascular procedures. Thrombosis plays a key role in the development of restenosis. Thrombin-specific inhibitors have been considered as one type of candidates for the prevention of restenosis. Previous studies by our group demonstrated that a novel thrombin-specific inhibitor, hirulog-like peptide (HLP), reduced balloon catheter-induced neointima formation in rat carotid arteries. The present study examined the effect of HLP on angioplasty-induced restenosis in carotid arteries of atherosclerotic rabbits. New Zealand white rabbits were subject to air desiccation of the lumen of the right carotid arteries, then received high cholesterol/fat diet for 3 weeks. The rabbits were intravenously infused with HLP (1.6 mg/(kg/h)) or saline (n=7 per group) for 4 h started before angioplasty which dilated atherosclerotic lesions in right common carotid artery. Four weeks after the angioplasty, neointimal area, stenosis and neointima/media ratio in injured carotid arteries were reduced in atherosclerotic rabbits treated with HLP compared to saline controls by 62, 39 and 59% (P<0.05). The expression of tissue factor (TF) and transforming growth factor (TGF)-beta in the neointima of carotid arteries of rabbits treated with HLP was significantly weaker than saline controls (P<0.05 or <0.01). Activated partial thromboplastin time and bleeding time in HLP-treated rabbits were not significantly prolonged compared to controls. The results of the present study suggest that HLP may substantially reduce angioplasty-induced restenosis in atherosclerotic rabbits without increasing bleeding tendency. The inhibition on the expression of TF and TGF-beta in the neointima of the arterial wall may contribute to the preventive effect of HLP on restenosis in atherosclerotic rabbits.
Atherosclerosis 2003 Jul
PMID:Hirulog-like peptide reduces restenosis and expression of tissue factor and transforming growth factor-beta in carotid artery of atherosclerotic rabbits. 1286 Feb 48

Increasing evidence suggests that atherosclerosis is an inflammatory disease promoted by hypercholesterolemia. The role of adaptive immunity has been controversial, however. We hypothesized that proatherogenic T cells are controlled by immunoregulatory cytokines. Among them, TGF-beta has been implied in atherosclerosis, but its mechanism of action remains unclear. We crossed atherosclerosis-prone ApoE-knockout mice with transgenic mice carrying a dominant negative TGF-beta receptor II in T cells. The ApoE-knockout mice with disrupted TGF-beta signaling in T cells exhibited a sixfold increase in aortic lesion surface area, a threefold increase in aortic root lesion size, and a 125-fold increase in aortic IFN-gamma mRNA when compared with age-matched ApoE-knockout littermates. When comparing size-matched lesions, those of mice with T cell-specific blockade of TGF-beta signaling displayed increased T cells, activated macrophages, and reduced collagen, consistent with a more vulnerable phenotype. Ab's to oxidized LDL, circulating T cell cytokines, and spleen T cell activity were all increased in ApoE-knockout mice with dominant negative TGF-beta receptors in T cells. Taken together, these results show that abrogation of TGF-beta signaling in T cells increases atherosclerosis and suggest that TGF-beta reduces atherosclerosis by dampening T cell activation. Inhibition of T cell activation may therefore represent a strategy for antiatherosclerotic therapy.
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PMID:Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. 1456 88

Both inflammation and genetics play an important role in the pathogenesis of atherosclerosis and coronary artery disease. Epidemiological studies have investigated the association between coronary artery disease (CAD) and gene polymorphisms of the inflammatory molecules tumor necrosis factors (TNF) alpha and beta, transforming growth factors (TGF) beta-1 and beta-2, interleukin (IL)-1 and its receptor antagonist (IL-1ra), CD14 (the receptor for lipopolysaccharide), P- and E-selectins, and platelet endothelial cell adhesion molecule (PECAM)-1. Current evidence suggests that the TNF polymorphisms explored so far are not linked to CAD. The majority of studies conducted showed no significant association between TGFbeta-1 and coronary atherosclerosis, but the data currently available are somewhat controversial. Some polymorphisms may increase the risk of myocardial infarction (MI) within specific ethnic groups or in certain populations. The association between the IL-1 system and atherosclerosis is complex and may vary as a result of a number of factors, such as stage of disease, clinical phenotype, and possibly population characteristics. The E-selectin gene (SELE) Arg128, 98T, and Phe554 alleles may increase the risk of atherosclerosis, but not necessarily the risk of MI. This association seems to be more pronounced in younger patients. The PECAM1 Leu125Val and Ser563Asn polymorphisms may increase the risk of atherosclerosis but not necessarily of MI. This association may be especially important in patients with a low risk for developing atherosclerosis. Current data indicate that screening for CD14-260C/T genotypes is unlikely to be a useful tool for risk assessment and it remains unclear whether CD14 polymorphisms significantly increase the risk of MI. The associations between candidate gene polymorphisms and CAD are complex as a consequence of pleiotropy, variations with age, selection due to the high lethality of the disease, and interactions with other genes and environmental factors. Nonetheless, although the current data is preliminary and partly conflicting, it does provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of CAD.
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PMID:Genetic polymorphisms in cytokine and adhesion molecule genes in coronary artery disease. 1457 20


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