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)

Migration of medial smooth muscle cells (SMC) into the intima is important in intimal thickening of atherosclerotic tissues. To study the functions of three isoforms of platelet-derived growth factor (PDGF) in atherosclerosis, we investigated their effects on SMC migration by Boyden's chamber method. Although PDGF-AB and PDGF-BB enhanced SMC migration dose-dependently, PDGF-AA did not enhance SMC migration, but instead inhibited SMC migration induced by PDGF-AB or PDGF-BB. PDGF-AA also inhibited SMC migration induced by two other migration factors, fibronectin and SMC-derived migration factor. PDGF-AA is considered to be coexpressed with transforming growth factor (TGF)-beta 1 in atherosclerotic tissues. Treatment of SMC with TGF-beta 1 reduced an autocrine migration activity from SMC. Studies using anti-PDGF antibody revealed that an increased secretion of PDGF-AA by TGF-beta 1 caused the reduced migration activity. cAMP increase by forskolin and dibutyryl cAMP suppressed SMC migration, whereas cAMP decrease by pertussis toxin had no effects on PDGF-AA-suppressed migration. In contrast, staurosporine, an inhibitor of protein kinase C, enhanced SMC migration and neutralized the inhibitory effect of PDGF-AA. These findings suggest that PDGF-AA regulates SMC migration in intimal thickening in atheroma formation and that protein kinase C may play an important role in the inhibitory mechanism of PDGF-AA.
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PMID:Regulatory effects of platelet-derived growth factor-AA homodimer on migration of vascular smooth muscle cells. 133 Oct 68

Vascular cell adhesion molecule-1 (VCAM-1) is induced on endothelial cells by inflammatory cytokines, and binds mononuclear leukocytes through the integrin very late antigen-4 (VLA-4) (alpha 4 beta 1). This adhesion pathway has been implicated in a diverse group of physiological and pathological processes, including B cell development, leukocyte activation and recruitment to sites of inflammation, atherosclerosis, and tumor cell metastasis. The major form of VCAM-1 (VCAM-7D) has seven extracellular immunoglobulin (Ig)-like domains, of which the three NH2-terminal domains (domains 1-3) are similar in amino acid sequence to domains 4-6. By functional analysis of VCAM-7D relative to VCAM-6D (a minor 6-domain form of VCAM-1 in which domain 4 is deleted because of alternative splicing), and chimeric constructs between VCAM-1 and its structural relative intercellular adhesion molecule-1 (ICAM-1), we show that either the first or the homologous fourth domain of VCAM-1 is required for VLA-4-dependent adhesion. Either of these binding sites can function in the absence of the other. When both are present, cell binding activity is increased relative to monovalent forms of the molecule. The homologous binding regions appear to have originated by internal duplication of a portion of a monovalent ancestral gene, before the mammalian radiation. Thus VCAM-1 exemplifies evolution of a functionally bivalent cell-cell adhesion molecule by intergenic duplication. We have also produced a new class of anti-VCAM-1 monoclonal antibodies that block domain 4-dependent adhesion, and demonstrate that both binding sites participate in the adhesion function of VCAM-1 on endothelial cells in vitro. Therefore both sites must be blocked in clinical, animal, or in vitro studies depending on the use of anti-VCAM-1 antibodies to inactivate the VCAM-1/VLA-4 adhesion pathway.
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PMID:Activated endothelium binds lymphocytes through a novel binding site in the alternately spliced domain of vascular cell adhesion molecule-1. 137 28

Several studies during recent years have demonstrated the potential for vascular smooth muscle cells (SMC) and dermal fibroblasts to participate in immune interactions such as antigen presentation and alloreactivity. The molecular interactions mediating lymphocyte adhesion to these mesenchymal cells have, however, not previously been characterized in detail. In the present study we demonstrate ICAM-1 (CD54) expression by cultured human SMC and its up-regulation by IL-1, IFN-gamma, and bacterial lipopolysaccharide. Monoclonal antibodies were used to define the molecular interactions in the adhesion of 51Cr-labelled T lymphoblasts to adherent SMC and fibroblasts. ICAM-1 appeared to mediate adhesion of T lymphocytes by binding to the beta 2-integrin CD11a/CD18 (LFA-1) expressed by the lymphoblasts. We present evidence for the involvement of at least three different mechanisms in the adhesion of activated T lymphocytes to cultured fibroblasts. It was found that beta 2-integrin-mediated interaction could only account for less than half of the binding activity. The remaining adhesion was partly mediated by beta 1-integrins, presumably via VLA-5 since an anti-VLA-5 antibody and an RGD-containing peptide blocked adhesion to the same degree. However, antibodies to beta 1-, beta 2-, and beta 3-integrin subunits added together only inhibited adhesion by approximately 50%. The residual adhesion could be blocked by inhibition of cell metabolism and was increased by stimulation of the lymphocytes with phorbol ester, suggesting involvement of other, as yet undefined, adhesion molecules. The molecular interactions between lymphocytes and mesenchymal cells demonstrated in this study may have implications in several inflammatory conditions such as vasculitis, atherosclerosis, and connective tissue diseases.
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PMID:Adhesion of activated T lymphocytes to vascular smooth muscle cells and dermal fibroblasts is mediated by beta 1- and beta 2-integrins. 138 Jan 79

The human atherosclerotic plaque contains large numbers of T lymphocytes and macrophages; this indicates that immune and inflammatory mechanisms may be important factors in the pathogenesis of atherosclerosis. A significant proportion of the T lymphocytes express activation markers, which suggests that they may be stimulated by local antigens, proliferate in response to such antigens, and secrete lymphokines that could serve as paracrine factors in the arterial tissue. However, it is not known, whether plaque T lymphocytes constitute a homogeneous population of clonally proliferating cells or represent a heterogeneous mixture of cells with different immunologic specificities. Clonally-derived T lymphocytes can be identified since they carry identical T cell antigen receptor (TCR) genes. These genes rearrange during T cell ontogeny resulting in TCR genes and TCR proteins that are unique for each T cell clone. We have now employed TCR gene analysis to T lymphocytes derived from atherosclerotic plaques in order to determine their clonal composition. T lymphocytes were isolated from carotid endarterectomy samples and cultured after limiting dilution cell cloning. TCR genes were analyzed by Southern blotting using probes for the TCR gamma (J gamma 2) and TCR beta (C beta 1) genes. TCR gene rearrangement patterns were totally heterogeneous, indicating that plaque T lymphocytes constitute a polyclonal population of cells. This suggests that the T cells are either recruited to the plaque in an activated state or activated locally by mechanisms that do not lead to clonal proliferation.
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PMID:Polyclonal origin of T lymphocytes in human atherosclerotic plaques. 183 15

Transforming growth factor (TGF)-beta 1 may have different effects on cell proliferation depending on many conditions. This paper clarifies the effects of various conditions on the effect of TGF-beta 1 on proliferation of cultured rabbit aortic smooth muscle cells (SMC) and also the time of its action during the cell cycle. TGF-beta 1 at 10-10,000 pg/ml inhibited DNA synthesis of SMC in the G0 stage derived from normal media or atheromatous intima stimulated by either platelet-derived growth factor (PDGF), fibroblast growth factor, SMC-derived growth factor, or fetal bovine serum (FBS). TGF-beta 1 also inhibited the growth of SMC in the growing state stimulated by either PDGF or FBS. TGF-beta 1 was effective only when added to the culture within 2 h after stimulation of the G0 state SMC with PDGF. It also inhibited increase in transcription of the c-myc protooncogene on stimulation of SMC with PDGF. These data suggest that TGF-beta 1 inhibited proliferation of SMC irrespective of the cell phenotype, growth conditions, and growth factors present and that it exerted this inhibitory effect during the time of the G0/G1 transition.
Atherosclerosis 1991 Jun
PMID:Effects of transforming growth factor-beta 1 on growth of aortic smooth muscle cells. Influences of interaction with growth factors, cell state, cell phenotype, and cell cycle. 189 88

Thrombin, in addition to its central role in hemostasis, possesses diverse cellular bioregulatory functions implicated in wound healing, inflammation, and atherosclerosis. In the present study we demonstrate that thrombin molecules modified either at the procoagulant or catalytic sites induce endothelial cell (EC) adhesion, spreading, and cytoskeletal reorganization. The most potent adhesive thrombin analogue (NO2-alpha-thrombin) was obtained by nitration of tyrosine residues. The cell adhesion promoting activity of NO2-alpha-thrombin was blocked upon the formation of thrombin-antithrombin III (ATIII) complexes and by antiprothrombin antibodies, but was unaffected by hirudin. Arg-Gly-Asp-containing peptides, fully inhibited EC adhesion to NO2-alpha-thrombin, while synthetic peptides corresponding to thrombin "Loop B" mitogenic site and the thrombin-derived chemotactic fragment "CB67-129", were uneffective. Immunofluorescence studies indicated that EC adhesion to NO2-alpha-thrombin was followed by cell spreading, actin microfilament assembly, and formation of focal contacts. By the use of specific antibodies, the vitronectin (vn) receptor (alpha v beta 3) was found to be localized in clusters upon cell adhesion to NO2-alpha-thrombin. An anti alpha v beta 3 antibody blocked EC adhesion and spreading while antifibronectin (fn) receptor (alpha 5 beta 1) antibodies were uneffective. While native thrombin exhibited a very low cell attachment activity, thrombin that was incubated at 37 degrees C before coating of plastic surfaces induced EC attachment and spreading. We propose that under certain conditions the naturally hindered RGD domain within thrombin is exposed for interaction with alpha v beta 3 on EC. This in turn promotes cell adhesion, spreading, and reorganization of cytoskeletal elements, which may altogether contribute to repair mechanisms in the disturbed vessel wall. This study defines a new biological role of thrombin and characterizes a new recognition mechanism on EC for this molecule.
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PMID:An Arg-Gly-Asp sequence within thrombin promotes endothelial cell adhesion. 198 65

Sympathetic activation appears to accelerate the development of atherosclerosis, an effect that may be inhibited by beta-receptor blockade. It is unclear, however, which mechanisms mediate this effect. In view of the significance attached to endothelial injury in the initial phases of atherogenesis, we decided to test whether sympathetic activation might lead to an increase in endothelial injury. Chloralose anesthesia was used to induce sympathetic activation and the presence of intracellular IgG as a criterion of endothelial cell injury. The beta 1-selective beta-blocker metoprolol was used to evaluate if the effect(s) of sympathetic activation might be mediated by beta 1-adrenoceptors. In normal rabbits, the frequency of injured endothelial cells in unbranched areas of the thoracic aorta was 0.23%, compared with 1.93% in circumostial areas. Chloralose anesthesia caused significant increases in blood pressure, heart rate, and plasma norepinephrine, that is, caused sympathetic activation, and led to an approximately fivefold increase in the number of injured cells both in unbranched and in circumostial areas. This increase was totally inhibited by metoprolol pretreatment, indicating that it was mediated by beta 1-receptors. These observations suggest one possible mechanism that may connect sympathetic activation with atherogenesis and explain why beta-blockade protects against atherosclerosis.
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PMID:Experimental sympathetic activation causes endothelial injury in the rabbit thoracic aorta via beta 1-adrenoceptor activation. 217 50

The effects of 3 beta-blockers with different pharmacological properties (non-selective: propranolol; beta 1-selective: metoprolol; and with intrinsic sympathomimetic activity: pindolol) were comparatively studied on LDL and lipid metabolism in human fibroblasts. At 10(-4) M, propranolol increased low density lipoprotein binding, uptake and degradation by 1.5-, 2.2- and 1.8-fold, respectively, whereas metoprolol and pindolol had no effect. This effect of propranolol is mainly due to an increase in LDL receptor number. Propranolol also enhanced sterol, triacylglycerol, fatty acid and phospholipid synthesis by 2-3-fold from sodium acetate. Cholesterol esterification by oleic acid was significantly and specifically decreased 4-fold by propranolol. Metoprolol and pindolol affect neither sterol synthesis nor cholesterol esterification. Pretreatment of cultured fibroblasts with propranolol induced an increase in hydroxymethyl-glutaryl-coenzyme A reductase activity and a decrease in acyl-coenzyme A: cholesterol-O-acyltransferase (ACAT) activity. Propranolol inhibited the induction of ACAT activity by exogenous cholesterol. Preincubation of a cell-free extract with propranolol also induced inhibition of ACAT activity. Propranolol decreased the cholesteryl ester content of cultured cells. These effects of propranolol on LDL and cholesterol metabolism might be related to the amphiphilic properties of the drug and suggest an effect on the cholesterol intracellular traffic. The decrease in cholesterol esterification and in the cholesteryl ester cellular level induced by propranolol may be involved in its antagonizing effect on experimental atherogenesis.
Atherosclerosis 1990 Mar
PMID:The antihypertensive drug propranolol enhances LDL catabolism and alters cholesterol metabolism in human cultured fibroblasts. 232 24

Metoprolol has been on the market for 10 years; the research, however, started nearly 20 years earlier and clinical research some 17 years ago. Metoprolol has been and is still subject to intensive research, which has resulted in evidence for its cardiovascular protective effects in coronary heart disease, cardiovascular hypertrophy and atherosclerosis. The properties making the beta 1-selective blocker metoprolol a cardioprotective drug and pharmaceutical development improving the qualities of the substance are also discussed in this review.
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PMID:Ten years of clinical experience with metoprolol. 248 Nov 76

The effects of the highly beta 1-selective beta-blocker betaxolol (Kerlone) on carbohydrate and lipid metabolism in type II diabetic subjects were compared in a cross over study with those of a diuretic (xipamide-triamterene combination, Neotri). Betaxolol significantly lowered blood pressure with a tendency to better efficacy than the diuretic. The betaxolol-induced decrease in heart rate could be a contributing factor in attenuating the progression of atherosclerosis. No significant alterations were observed in postprandial blood glucose, glycosylated haemoglobin and 24-h urinary glucose excretion. The lack of noticeable influence on the carbohydrate metabolism during 4-week therapy is presumably related to the high beta 1-selectivity of betaxolol. Considering that diabetic hypertensive patients are at high risk for atherosclerosis it appears also favourable that betaxolol did not increase triglyceride levels and even decreased total cholesterol. The protective effect of beta-Blockers has been well established in the secondary and primary prevention of cardiovascular diseases. Especially diabetic patients might be expected to benefit from this therapy, if given preferably as beta 1-selective blocker that impairs carbohydrate and lipid metabolism in lesser extent.
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PMID:[The effect of the beta 1 selective beta blocker, betaxolol, on metabolism in type II diabetics]. 256 9


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