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)

Oxidized LDL (Ox-LDL) plays atherogenic roles, whereas thrombospondin-1 (TSP-1) is thought to be anti-atherogenic through activation of TGF-beta that contributes to plaque stabilization. Ox-LDL was prepared by incubating of human LDL with CuSO4. Effect of Ox-LDL on TSP-1-induced TGF-beta activation was examined in the present study. Incubation of Ox-LDL with mouse peritoneal macrophages for 3 days resulted in reduction in amounts of active TGF-beta in the culture medium by 70-78% when compared with that of parallel incubation without Ox-LDL. TSP-1 could enhance conversion of latent TGF-beta1 into active TGF-beta1 in a cell-free system. This TSP-1-mediated latent TGF-beta1 activation was inhibited by 30% by Ox-LDL, suggesting the possible interaction of Ox-LDL with TSP-1. Incubation of TSP-1 with [125I]Ox-LDL or [125I]LDL, followed by immunoprecipitation with an anti-TSP-1 antibody demonstrated that a significant amount of [125I]Ox-LDL was co-precipitated with TSP-1 while precipitation of [125I]LDL was negligible. Furthermore, upon TSP-1-conjugated Sepharose 4B affinity chromatography, both [125I]Ox-LDL and [125I]latent TGF-beta1 bound to the affinity gel were eluted by unlabeled Ox-LDL. These findings indicate that Ox-LDL interacts with TSP-1 and suppresses subsequent TSP-1-dependent TGF-beta activation, revealing a novel atherogenic function of Ox-LDL.
Atherosclerosis 2005 Nov
PMID:Specific interaction of oxidized low-density lipoprotein with thrombospondin-1 inhibits transforming growth factor-beta from its activation. 1590 58

Cardiovascular events are the leading causes of morbidity and mortality in renal transplant recipients (RTR). Given the role of inflammation in atherosclerosis, the contribution of functional polymorphisms of cytokines to cardiovascular diseases (CVD) was assessed in RTR in this study. Polymorphisms of tumour necrosis factor alpha (TNF-alpha) gene [-308 (G-->A), -238 (G-->A)], interleukin-10 (IL-10) gene [-1082(A-->G), -819 (T-->C), -592 (A-->C)], transforming growth factor beta 1 (TGF-beta1) gene [codon 10 (T-->C), codon 25 (G-->C)], carotis intima media thickness (CIMT), left ventricular mass index (LVMI), 24-h ambulatory blood pressure and serum lipoprotein homocysteine level, erythrocyte sedimentation rate, serum C-reactive protein (CRP) and serum fibrinogen level of RTR were determined. Seventy-two RTR (26 cadaveric allograft, 46 living-related allograft, 43 male, 29 female) were included in this study. LVMI were similar in TNF-alpha, IL-10 and TGF-beta1 genotypes. Right and left CIMT were higher in TT genotype (n = 16) than CT (n = 46) and CC (n = 10) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (RCIMT, 7.7 +/- 2.2 mm vs. 7.0 +/- 1.4 mm vs. 5.9 +/- 1.4 mm, P = 0.025; LCIMT, 8.5 +/- 2.5 mm vs. 7.0 +/- 1.3 mm vs. 6.1 +/- 1.2 mm, P = 0.002). Lipoprotein (a) level of TT genotype (35.5 +/- 22.5 mg/dl) was higher than CC (4.1 +/- 2.8 mg/dl) and CT (20.4 +/- 11.2 mg/dl) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (P = 0.037). High producers of cytokine IL-10 -1082 [GG (n = 22) vs. AA + AG (n = 50)] and low producers of TGF-beta codon 25 [GC + CC (n = 17) vs. GG (n = 55)] had lower IMT of carotid artery but the difference did not reach statistical significance (P > 0.05). The CIMT of renal transplant patients was similar in IL-10 (-819, -592) and TNF-alpha (-308, -238) genotypes. No difference was observed in 24-h ambulatory blood pressure levels, serum lipoproteins, plasma homocysteine level, erythrocyte sedimentation rate, serum CRP, serum fibrinogen level in IL-10, TNF-alpha and TGF-beta1 genotypes. Besides the well-known factors, TGF-beta1 gene polymorphisms might play a role in CVD in RTR even at early stages of asymptomatic atherosclerosis.
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PMID:Impact of cytokine gene polymorphism on cardiovascular risk in renal transplant recipients. 1591 Feb 94

Although it has been demonstrated that carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs) cause progression of atherosclerosis, the underlying mechanism remains unclear. In the present study, we aimed to investigate whether DNA binding events are critically involved in the progression of PAH-mediated atherogenesis. Apolipoprotein E knockout mice were orally (24 wk, once/wk) exposed to 5 mg/kg benzo[a]pyrene (B[a]P), or its nonmutagenic, noncarcinogenic structural isoform benzo[e]pyrene (B[e]P). 32P-postlabeling of lung tissue confirmed the presence of promutagenic PAH-DNA adducts in B[a]P-exposed animals, whereas in B[e]P-exposed and vehicle control animals, these adducts were undetectable. Morphometrical analysis showed that both B[a]P and B[e]P caused an increase in plaque size, whereas location or number of plaques was unaffected. Immunohistochemistry revealed no differences in oxidative DNA damage (8-OHdG) or apoptosis in the plaques. Also plasma lipoprotein levels remained unchanged after PAH-exposure. However, T lymphocytes were increased > or =2-fold in the plaques of B[a]P- and B[e]P-exposed animals. Additionally, B[a]P and to a lesser extent B[e]P exposure resulted in increased TGFbeta protein levels in the plaques, that was mainly localized in the plaque macrophages. In vitro studies using the murine macrophage like RAW264.7 cells showed that inhibition of TGFbeta resulted in decreased tumor necrosis factor (TNF) alpha release, suggesting that enhanced TGFbeta expression in the plaque macrophages contributes to the proinflammatory effects in the vessel wall. In general, this inflammatory reaction in the plaques appeared to be a local response since peripheral blood cell composition (T cells, B cells, granulocytes, and macrophages) was not changed upon PAH exposure. In conclusion, we showed that both B[a]P and B[e]P cause progression of atherosclerosis, irrespective of their DNA binding properties. Moreover, our data revealed a possible novel mechanism of PAH-mediated atherogenesis, which likely involves a TGFbeta-mediated local inflammatory reaction in the vessel wall.
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PMID:Polycyclic aromatic hydrocarbons induce an inflammatory atherosclerotic plaque phenotype irrespective of their DNA binding properties. 1593 34

Current theories suggest that atherosclerosis, plaque rupture, stroke, and restenosis after angioplasty may involve defective apoptotic mechanisms in vascular cells. Prior work has demonstrated that cells from human atherosclerotic lesions, and cells from the aorta of aged rats, exhibit functional resistance to apoptosis induced by TGF-beta and glucocorticoids. The present studies demonstrate that human lesion-derived cells (LDC) are also resistant to apoptosis induced by fas ligation compared to cells derived from the adjacent media, and that in vitro expansion of LDC causes acquired resistance to apoptosis. Microarray profiling of fas-resistant versus sensitive cells identified a set of genes including STATs, caspase 1, cyclin D1, Bcl-xL, VDAC2, and BAD. The STAT proteins have been implicated in resistance to apoptosis, potentially via their ability to modulate caspase 1 (ICE), Bcl-xL, and cyclin D1 expression. Western blot analysis of sensitive and resistant LDC clonal lines confirmed increases in cyclin D1, STAT6, Bcl-xL, and BAD, with decreased expression of caspase 1. Thus, transcript profiling has identified a potential pathway of apoptotic regulation in subsets of lesion cells. The resistant phenotype may contribute to plaque stability and excessive vascular repair, while sensitive cells may be involved in plaque rupture and infarction. The data suggests both genetic interventions and novel small-molecule inhibitors that may be effective modulators of apoptosis in atherosclerosis, angina, and in-stent restenosis.
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PMID:Genomic profiling of acquired resistance to apoptosis in cells derived from human atherosclerotic lesions: potential role of STATs, cyclinD1, BAD, and Bcl-XL. 1600 68

Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.
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PMID:Oral tolerance. 1604 53

Vascular smooth muscle cells (VSMCs) constitute the major cellular component of the vessel tunica media. VSMC proliferation is a key feature in developing vessels and pathological states such as atherosclerosis and restenosis. Transforming growth factor (TGF)-beta is a key regulator of VSMCs, but its effect on VSMC proliferation and apoptosis are controversial. Here, we characterized TGF-beta effects on basal-, serum-, and platelet-derived growth factor-BB-induced primary mouse VSMC proliferation. TGF-beta led to potent growth inhibition of VSMCs isolated from normal mouse aortae without inducing apoptosis. Growth inhibition by TGF-beta was due to G0/G1 arrest. Next, we explored distinct signaling pathways activated by TGF-beta and the effects of pharmacological inhibition of these. TGF-beta led to activation of Smad2/3, p38, p42/44, and c-Jun NH2-terminal kinase (JNK) pathways, assessed by phosphorylation, immunofluorescence, and reporter gene analysis. TGF-beta-dependent growth inhibition was specifically attenuated by pharmacological blockade of the TGF-beta type I receptor (TbetaRI) kinase or p38 mitogen-activated protein kinase pathways, whereas blockade of p42/44 or JNK kinases did not influence the effect of TGF-beta. TbetaRI kinase inhibition blocked all downstream pathways including Smad and p38 phosphorylation. In contrast, p38 inhibition did not alter Smad function, as assessed by translocation or reporter gene expression, but selectively inhibited p38 activity. These results demonstrate that TGF-beta acts as a potent antiproliferative mediator in VSMCs, irrespective of the proliferative stimulus, without inducing apoptotic effects. The anti-proliferative effect of TGF-beta is due to G0/G1 arrest and mediated primarily by the p38 pathway, suggesting that p38 kinase is central to TGF-beta-mediated growth inhibition in primary mouse VSMCs.
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PMID:Transforming growth factor-beta-dependent growth inhibition in primary vascular smooth muscle cells is p38-dependent. 1612 Aug 11

Upregulation of plasminogen activator inhibitor type 1 (PAI-1) expression is a critical mechanism through which transforming growth factor-beta1 (TGF-beta1) accelerates intimal growth. The aim of this study was to identify signaling pathways through which TGF-beta1 upregulates PAI-1 expression in endothelial cells (EC) and test interventions for blocking these pathways. We transduced cultured bovine EC with an adenoviral vector containing the PAI-1 promoter fused to a beta-galactosidase reporter gene. We used these cells, along with vectors expressing potential modifiers of TGF-beta1 signaling and pharmacologic antagonists of mitogen-activated protein kinase (MAPK) pathways to identify key mediators of basal and TGF-beta1-regulated PAI-1 expression. Basal activity of the PAI-1 promoter was directly correlated with Ras activation and was blocked by a dominant negative (DN) type I TGF-beta receptor. TGF-beta1-stimulated activity of the PAI-1 promoter did not require Ras activation, and was lessened or eliminated by expression of either DN type I or type II TGF-beta receptors and by inhibition of either of two MAPKs: MEK and p38. Our results suggest unanticipated pathways of TGF-beta1 signaling in EC and point to new strategies to limit TGF-beta1-induced vascular disease.
Atherosclerosis 2006 May
PMID:Identification of intracellular pathways through which TGF-beta1 upregulates PAI-1 expression in endothelial cells. 1613 37

Accelerated atherosclerosis in dialysis patients is characterized by severe vascular calcification, and the magnitude of vascular calcification is associated with increased cardiovascular mortality. Calcification-dependent arterial stiffness is considered to be a major determinant of cardiac failure in uremia. Fetuin-A/alpha(2)-Heremans-Schmid glycoprotein is an abundant serum protein with powerful calcification inhibitory properties. Fetuin-A deficiency was recently linked to cardiovascular mortality in dialysis patients. Fetuin-A knockout (fetuin-KO) mice spontaneously develop widespread soft tissue calcification, including significant myocardial calcification, whereas larger arteries are spared. Therefore, this investigation offers the unique opportunity to study the functional role of isolated myocardial calcification independent of arterial stiffness by assessing the hemodynamics of fetuin-KO mice. Cardiac output in fetuin-KO mice was lower than in wild-type mice (fetuin-KO 1.81 +/- 0.18 versus WT 2.45 +/- 0.29 ml/min per g; P < 0.005), and fetuin-KO mice were refractory to dobutamine stimulation. Left ventricular relaxation was significantly impaired in fetuin-KO hearts with the relaxation index reduced by 23% (P < 0.005). After ischemia, fetuin-KO hearts displayed a continuous decline in left ventricular developed pressure after the initial phase of reperfusion, resulting in 77 +/- 15% of preischemic left ventricular developed pressure (P < 0.05 versus wild-type). In fetuin-KO mice, dystrophic cardiac calcification, with myocardial calcium contents increased 60-fold, was associated with profound induction of profibrotic TGF-beta and downstream collagen and fibronectin mRNA synthesis. In conclusion, independent of arterial stiffness, calcification-associated "myocardial stiffness" characterized by cardiac fibrosis, diastolic dysfunction, impaired tolerance to ischemia, and catecholamine resistance thus may constitute an underestimated cardiovascular risk factor that contributes to cardiac failure in calcification-prone states.
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PMID:Myocardial stiffness, cardiac remodeling, and diastolic dysfunction in calcification-prone fetuin-A-deficient mice. 1617

Insulin resistance has been implicated as one possible factor that links visceral obesity to unfavourable metabolic and cardiovascular consequences. However, the mechanism whereby adipose tissue causes alterations in insulin action remains unclear. White adipose tissue is secreting several hormones, particularly leptin and adiponectin, and a variety of other protein signals: the adipocytokines. They include proteins involved in the regulation of energy balance, lipid and glucose metabolism as well as angiogenesis, vascular and blood pressure regulation. Visceral obesity and inflammation within white adipose tissue may be a crucial step contributing to the emergence of insulin resistance, type 2 diabetes and atherosclerosis. A growing list of adipocytokines involved in inflammation (IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, TGF-beta,) and the acute-phase response (serum amyloid A, PAI-1) have been found to be increased in the metabolic syndrome. It is, however, unclear as to the extent adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and how they may affect the insulin-dependent tissues. This review describes the role of the currently known adipocytokines and hormones released by adipose tissue in generating the insulin resistance state and the chronic inflammatory profile which frequently goes together with visceral obesity.
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PMID:Review article: adipocytokines and insulin resistance. 1622 63

5-lipoxygenase (5LO) catalyzes formation of leukotrienes, mediators with roles in several inflammatory disorders, including atherosclerosis. The human 5LO gene promoter contain multiple GC-boxes. The relevance of these for expression of 5LO in the human monocytic cell line Mono Mac 6 (MM6) was studied. A downregulating effect of the GC-box binding compound mithramycin indicated that GC-rich sequences in the 5LO gene promoter are important for expression of native 5LO. In DNase I footprinting, mithramycin and Sp1 protected known GC-boxes, but also a novel Sp1 binding site was found, comprising 20 bp upstream of the major transcription initiation site, beside an Initiator-like sequence. Mutation of this site reduced Sp1 binding and expression of reporter genes in MM6 cells, compatible with a function as basal promoter element for the TATA-less 5LO gene. When differentiation was induced by TGFbeta and vitamin D(3), 5LO expression became prominent, but expression levels of Sp1/3 and Egr-1 were the same as for control cells. Also, 5LO reporter gene activity in transiently transfected MM6 cells was insensitive to differentiation. Thus, the GC-rich part of the 5LO gene promoter, including a novel Sp1 site, appear important for basal (rather than upregulated) transcription of 5LO in MM6 cells.
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PMID:GC-rich sequences in the 5-lipoxygenase gene promoter are required for expression in Mono Mac 6 cells, characterization of a novel Sp1 binding site. 1641 24


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