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 pathogenesis of atherosclerosis is hypothesized to occur as a response to various forms of injury to the lining arterial endothelial cells. The resulting endothelial alterations could potentially lead to interactions between platelets in the circulation and the underlying subendothelial connective tissue or with the altered endothelial cells themselves. Such interactions provide an opportunity for platelet degranulation and release of a platelet-derived growth factor. This factor has been shown in cell culture to be an extremely potent mitogen and will induce DNA synthesis and cell multiplication of a number of cells including smooth muscle cells, fibroblasts, and other mesenchymally derived cells. Chronic endothelial injury and repeated interactions between platelet-derived mitogens, plasma components, and the underlying arterial smooth muslce cells would promote the progression of the intimal proliferative lesions of atherosclerosis that lead to the clinical sequelae associated with this disease process.
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PMID:The pathogenesis of atherosclerosis. 37 62

Cilostazol, a cyclic AMP phosphodiesterase inhibitor, has been used as an antiplatelet agent. In the present study, we investigated the in vitro effect of cilostazol on DNA synthesis in rat aortic arterial smooth muscle cells (SMCs) in culture stimulated with fetal calf serum (FCS), platelet-derived growth factor (PDGF), insulin, or insulin-like growth factor-I (IGF-I). Micromolar concentrations of cilostazol inhibited [3H]thymidine incorporation into DNA and cell growth as determined by cell number and protein concentration. Treatment with cilostazol increased the intracellular concentration of cyclic AMP, suggesting that the inhibition of SMC proliferation by cilostazol may be mediated through increased levels of cyclic AMP. The results suggested that cilostazol, by interfering with the proliferation of arterial SMCs, may have potential to prevent initiation and progression of atherosclerosis.
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PMID:Effect of cilostazol, a cyclic AMP phosphodiesterase inhibitor, on the proliferation of rat aortic smooth muscle cells in culture. 128 92

The mitogenic and chemotactic potency of platelet-derived growth factor (PDGF) has linked this polypeptide to the pathogenesis of several disease states including atherosclerosis and neoplasia. We have reviewed the recent literature on aspects relating to the structure, distribution and biology of PDGF and its high-affinity cell-surface and intracellular receptors. In addition to platelets, several normal and tumor cells secrete the mitogen in one or more of three possible dimeric configurations. Alternative splicing of exon 6 in PDGF A-chain RNA results in the formation of two protein species with different carboxy-termini. Initially, it was thought that the longer A-chain variant was processed only by transformed cells. However, recent evidence indicates that alternative splicing occurs in several cells which express the A-chain, including early Xenopus embryos. The functional significance of the exon 6 product, a highly basic region spanned by 18 amino acid residues (A194-211), is not precisely clear. We have summarized recent findings which implicate roles for A194-211 in the processing, secretion, and mitogenesis of the A-chain homodimer, nuclear transport signalling, and heparin binding. Thus, alternative splicing could play an important role in the modulation of the functional properties of the PDGF A-chain variants per se and in the complex interactive network of polypeptide growth factors and cytokines.
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PMID:Platelet-derived growth factor and alternative splicing: a review. 128 70

Interactions among growth factors, cells, and extracellular matrix are critical to the regulation of directed cell migration and proliferation associated with development, wound healing, and pathologic processes. Here we report the association of PDGF-AB and -BB, but not PDGF-AA, with the extracellular glycoprotein SPARC. Complexes of SPARC and 125I-labeled PDGF-BB or -AB were specifically immunoprecipitated by anti-SPARC immunoglobulins. 125I-PDGF-BB and -AB also bound specifically to SPARC that was immobilized on microtiter wells or bound to nitrocellulose after transfer from SDS/polyacrylamide gels. The binding of PDGF-BB to SPARC was pH-dependent; significant binding was detectable only above pH 6.6. The interaction of SPARC with specific dimeric forms of PDGF affected the activity of this mitogen. SPARC inhibited the binding of PDGF-BB and PDGF-AB, but not PDGF-AA, to human dermal fibroblasts in a dose-dependent manner. The expression of SPARC and PDGF was minimal in most normal adult tissues but was increased after injury. Enhanced expression of both PDGF-B chain and SPARC was seen in advanced lesions of atherosclerosis. We suggest that the coordinate expression of SPARC and PDGF-B-containing dimers following vascular injury may regulate the activity of specific dimeric forms of PDGF in vivo.
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PMID:The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors. 131 Oct 92

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

Results of animal studies suggest that calcium antagonists can inhibit the development of experimentally induced atherosclerosis. Although the biological process underlying this phenomenon has not been fully elucidated, several mechanisms have been proposed. Notably, calcium antagonists may suppress free radical-induced damage of the vascular endothelial cells with the consequent transport of low-density lipoproteins across the vascular endothelium and the accumulation of the lipids in the intima. Studies have shown that calcium antagonists can inhibit the stimulatory effects of epidermal growth factor on intracellular calcium concentrations and DNA synthesis in cultured rat aortic smooth muscle cells, but not those of platelet-derived growth factor or somatomedin C. Further experimental studies have demonstrated that calcium antagonists stimulate prostacyclin production and inhibit 12-hydroxyeicosatetraenoic acid-induced vascular smooth muscle cell migration, therefore preventing platelet aggregation and intimal thickening, respectively. Despite the encouraging results in animals, comparatively few clinical studies have been undertaken to establish the efficacy of calcium antagonists in the prevention of cardiovascular disease in hypertensive patients. This, in part, is due to the technical difficulties associated with measuring coronary artery stenosis, but the recent development of a technique for the video-densitometric analysis of coronary angiograms has enabled stenotic regions to be quantified. Using this approach, a retrospective study has been undertaken of the efficacy of long-term treatment with a calcium antagonist on the progression of coronary atherosclerosis. Results are encouraging and a prospective long-term, multicenter trial is proposed.
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PMID:The role of calcium antagonists in the treatment of atherosclerosis and hypertension. 136 1

Injury to the vascular endothelium and the subsequent inflammatory response are considered prerequisites for the development of atherosclerosis. Platelet-derived growth factor (PDGF) production by and monocyte adhesion to aortic endothelial cells (EC) may participate in this inflammatory process and therefore are two potential targets for control by anti-inflammatory agents. Our previous studies have demonstrated that monocyte adhesion and PDGF production are stimulated by thrombin in EC. Here, we provide evidence that treatment of EC with the anti-inflammatory agent 3-deazaadenosine (c3Ado) effectively abolished thrombin-stimulated PDGF production and monocyte adhesion. c3Ado had no significant effect on either basal monocyte adhesion or constitutive PDGF production. c3Ado was also effective in negating monocyte adhesion induced by other agonists, such as interleukin-1, phorbol 12-myristate 13-acetate (PMA), and lipopolysaccharide. Northern analysis demonstrated that c3Ado significantly reduced thrombin- and PMA-stimulated steady-state levels of PDGF-A chain, PDGF-B chain, and endothelial-leukocyte adhesion molecule-1 (ELAM-1) mRNAs. Nuclear run-on studies demonstrated that a marked transcriptional activation of these genes by thrombin and PMA was abrogated by c3Ado treatment. The transcriptional rate of the alpha-tubulin gene was unaffected by the drug. Antibody binding studies with an anti-ELAM-1 monoclonal antibody 7A9 revealed that thrombin-stimulated EC expression of ELAM-1 was abolished by c3Ado, indicating that the suppression of ELAM-1 expression on EC surface may be a mechanism by which c3Ado interferes with monocyte adhesion. Experiments with the nucleoside transport inhibitor nitrobenzylthioinosine suggested that the transport of c3Ado into EC was required for its inhibitory activity. In addition, L-homocysteine thiolactone was found to potentiate the inhibitory activity of c3Ado, suggesting that the accumulation of intracellular c3Ado homocysteine may be the underlying mechanism by which c3Ado inhibits thrombin-induced EC function. Taken together, these results indicate that c3Ado may prove effective against vascular injury and inflammation through its ability to inhibit induction of both monocyte adhesion and PDGF production.
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PMID:3-Deazaadenosine inhibits thrombin-stimulated platelet-derived growth factor production and endothelial-leukocyte adhesion molecule-1-mediated monocytic cell adhesion in human aortic endothelial cells. 137 93

Vascular smooth muscle cell is a major cell component involved in the process of atherosclerosis. In the present study, we investigated the effects of platelet-derived growth factor (PDGF)-BB dimer on the expression of macrophage-colony stimulating factor (M-CSF) in vascular smooth muscle cells isolated from human umbilical artery. On Northern blot analysis of total RNAs isolated from smooth muscle cells, with human cDNA for M-CSF, a marked dose-dependent reduction of mRNA level was found in PDGF-BB-treated smooth muscle cells. Cellular production of M-CSF was estimated by immunoblot analysis of cell lysate with specific polyclonal antibody against recombinant human M-CSF. A concentration of 10 ng/ml PDGF-BB significantly reduced M-CSF mass in smooth muscle cells compared with that in the absence of PDGF-BB. These results suggest that PDGF-BB plays an important role in the cellular metabolism of vascular wall by regulating the rate of M-CSF production in vascular smooth muscle cells.
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PMID:Platelet-derived growth factor BB-dimer suppresses the expression of macrophage colony-stimulating factor in human vascular smooth muscle cells. 137 30

Activated platelets secrete from their alpha granules a protein-like factor which stimulates the uptake of oxidized low-density lipoprotein (Ox-LDL) by macrophages. The aim of the present study was to evaluate the effect of three purified proteins obtained from platelet alpha granules: platelet-derived growth factor (PDGF), platelet factor-4 (PF-4), and beta-thromboglobulin (B-TG), on the uptake of Ox-LDL by macrophages. Cellular degradation of Ox-LDL by the J-774 A.1 macrophage-like cell line, that was preincubated for 18 h at 37 degrees C, with increasing concentrations of partially purified PDGF, (designated PDGF-CMS-III) was increased by up to 36% in comparison to control cells preincubated without PDGF. This effect was due to PDGF-mediated increase in the number of macrophage receptors for Ox-LDL. The enhanced uptake of Ox-LDL by PDGF resulted in an increase in cellular cholesterol content. Preincubation of macrophages with two types of recombinant PDGF dimers (10 ng/ml), revealed that PDGF-BB stimulated Ox-LDL cellular degradation by 64%, whereas PDGF-AB demonstrated only 34% stimulation, in comparison to control cells that were not treated with PDGF. The stimulatory effect of PDGF-CMS-III and PDGF-AB were reduced by 20% and 28%, respectively, when incubated in the presence of H-7, a specific protein kinase C inhibitor. When macrophages were preincubated with B-TG, cellular uptake of Ox-LDL was reduced by up to 30% at 100 ng B-TG/ml. This effect, however, was obtained only when B-TG was present in the incubation medium. Cellular degradation of Ox-LDL was not affected by preincubation of the cells with PF-4. Pretreatment of PCM with anti-PDGF or anti-B-TG antibodies abolished the effects of PCM on Ox-LDL degradation by macrophages. PDGF, thus, may represent the protein-like factor present in PCM which stimulates Ox-LDL degradation by macrophages, whereas B-TG may have a role in the recognition of PCM particles by the macrophage scavenger receptor. Modulation of macrophage cholesterol content by proteins secreted from activated platelets may have an important role in foam cell formation and atherosclerosis.
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PMID:Proteins derived from platelet alpha granules modulate the uptake of oxidized low density lipoprotein by macrophages. 138 28

The effects of curcumin, an anti-inflammatory agent from Curcuma longa, on the proliferation of blood mononuclear cells and vascular smooth muscle cells were studied. Proliferative responses were determined from the uptake of tritiated thymidine. In human peripheral blood mononuclear cells, curcumin dose dependently inhibited the responses to phytohemagglutinin and mixed lymphocyte reaction at the dose ranges of 10(-6) to 3 x 10(-5) and 3 x 10(-6) to 3 x 10(-5) M, respectively. Curcumin (10(-6) to 10(-4) M) dose dependently inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by fetal calf serum. Curcumin had a greater inhibitory effect on platelet-derived growth factor-stimulated proliferation than on serum-stimulated proliferation. Cinnamic acid, coumaric acid and ferulic acid were much less effective than curcumin as inhibitors of serum-induced smooth muscle cell proliferation, suggesting that the cinnamic acid and ferulic acid moieties alone are not sufficient for activity, and that the characteristics of the diferuloylmethane molecule itself are necessary for activity. Curcumin may be useful as a new template for the development of better remedies for the prevention of the pathological changes of atherosclerosis and restenosis.
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PMID:Inhibitory effect of curcumin, an anti-inflammatory agent, on vascular smooth muscle cell proliferation. 142 14


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