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)

Recent studies have been reported indicating that angiotensin II may potentiate neointimal formation. In the present study, we examined the antagonistic effect of tranilast on angiotensin II. Losartan was used as the reference compound. First, tranilast inhibited the angiotensin II-induced contraction of rabbit aortic strips in a noncompetitive manner (pD'(2) = 3.7), whereas it had little effect on the contraction induced by noradrenaline or endothelin-l. Second, tranilast inhibited the binding of (125)I-labeled angiotensin II to angiotensin AT1 receptors in rat liver membranes with an IC(50) value of 289 mu M. Finally, functional antagonism of tranilast (100 and 300 mu M) was demonstrated by its blockade of angiotensin II (10(-8)M)-induced (45)Ca(2+) -efflux from human vascular smooth muscle cells (VSMC). However, tranilast (30-300 mu M) exerted no influence on PDGF-induced formation of inositol triphosphates which cause an increase in [Ca(2+)]i in human VSMC. The antagonistic activity of tranilast towards angiotensin II may be involved in part in preventing restenosis after percutaneous transluminal coronary angioplasty (PTCA).
Atherosclerosis 1996 Apr 05
PMID:Tranilast antagonizes angiotensin II and inhibits its biological effects in vascular smooth muscle cells. 912 91

Studies of PDGF-A, PDGF-B and PDGF receptor-beta knock-out mice have revealed critical functions for the PDGF-PDGF receptor signaling systems in the ontogeny of connective tissue cells: the mesangial cells of kidney glomeruli and the alveolar smooth muscle cells (SMC) of the lung. The phenotypes of the PDGF mutant mice have also shed light on the identity and functions of these cell types, as well as revealed analogies suggesting that common morphogenetic principles have evolved for use in different organs, involving related growth factors and cell types. Although the lethality of PDGF knock-out mice has not allowed an investigation of the role of PDGF in SMC of the vessel wall, regulation of PDGF and its receptors in adult vessels following injury is consistent with a role for PDGF in the fibroproliferative response in the intima that occurs as part of the pathogenesis of atherosclerosis. PDGF modulation of connective tissue synthesis may thus be critical to connective tissue phenotype and proliferation in both embryogenesis and pathogenesis.
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PMID:Platelet-derived growth factor: a key regulator of connective tissue cells in embryogenesis and pathogenesis. 915 Apr 45

Originally known to be a vasoconstrictor and thought to play a critical role in hypertension, angiotensin II has recently emerged to be important in inflammation, atherosclerosis and congestive heart failure. The expanding role of angiotensin II implies that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Recent data show that angiotensin II stimulates not only cytoplasmic tyrosine kinases including c-Src, focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2), but also may transactivate receptor tyrosine kinases such as Axl and PDGF by as yet undefined autocrine/paracrine mechanisms. Finally, tyrosine kinases, which mediate tyrosine phosphorylation of key signal mediators such as Shc, Raf, and phospholipase C-gamma following angiotensin II stimulation, remain to be defined. These tyrosine kinases, activated by angiotensin II, appear to be required for angiotensin II effects such as vasoconstriction, proto-oncogene expression, protein synthesis, and cell proliferation. Thus, it is important to understand angiotensin II-mediated signaling events, especially those related to tyrosine kinase activity, to develop new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle cells: role of tyrosine kinases. 921 88

Human atherosclerotic plaques are heterogeneous tissues containing a number of different cell types, including macrophages, smooth muscle, endothelial and other undefined mesenchymal-appearing cells. Significant numbers of macrophages are found in human atherosclerotic plaques and have been postulated to be a major source of growth factor production during atherogenesis. In vitro evidence suggested that macrophages synthesize PDGF and might therefore contribute to the growth of the vessel wall in atherosclerosis. However, examination of PDGF synthesis in human atheroma by in situ hybridization revealed that while smooth muscle, mesenchymal, and endothelial cells synthesize this growth factor macrophages did not. Our inability to detect PDGF mRNA in macrophages was not due to any problems with hybridization to this cell type. In situ hybridization studies on human atherosclerotic plaques have demonstrated that plaque macrophages contain many different mRNAs other than PDGF including tissue factor, factor XIII, apoprotein E, transforming growth factor beta, and tumor necrosis factor. Recent studies have indicated that macrophages may be a major source as well of another group of inflammatory cytokines which are members of the RANTES/SIS cytokine family. In situ hybridization studies on human carotid endarterectomy specimens using probes specific for the inflammatory cytokines RANTES, LD78, HIMAP, and MCP-1 revealed numerous cells containing the mRNAs encoding for these proteins (5%, 13%, 8%, and 16% of plaque cells respectively). This is in contrast to generally low level expression found in normal human arteries (< 1% of normal medial cells contain these mRNAs). Cells expressing these cytokines were often found associated with inflammatory zones in human atherosclerotic plaques. Serial section immunohistochemistry suggests that macrophages and/or T cells may synthesize these proteins. In addition to localization to macrophages MCP-1 expression was also detected in smooth muscle cells and mesenchymal-appearing cells with many of the morphological characteristics of cells previously seen to express PDGF. In vitro evidence suggests that these proteins may be chemotactic to monocytes and lymphocytes. The finding of increased expression of these mRNAs in human atheroma suggests they may play a role in monocyte trafficking into the atherosclerotic plaque.
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PMID:Local expression of inflammatory cytokines in human atherosclerotic plaques. 922 84

In vascular smooth muscle cells (SMCs), proliferation and migration contribute to lesion formation after arterial injury. In the cell cycle, several cyclin-dependent kinases (cdks) inhibitors are implicated in the regulating of cyclin-cdk activity such as p21Cip1, p16Ink4 and p27Kip1. Although Cip1 inhibits SMC proliferation, its effects on SMC migration are unknown. To test the hypothesis that Cip1 inhibits SMCs migration and proliferation, we transfected the Cip1 gene into a strain of rabbit aortic SMCs (SM3 cells). Both the spreading and the attachment of Cip1-transfected SM3 cells to extracellular matrices (ECMs) were inhibited compared to that of vector-transfected cells. In the modified Boyden's chamber assay the effect of fibronectin on the migratory activity of Cip1-transfected SM3 cells was significantly less than that of vector transfected cells in response to PDGF-BB. These data suggested that Cip1 inhibited both the migration and proliferation of SMC.
Atherosclerosis 1997 Jul 11
PMID:Inhibition of smooth muscle cell migration by the p21 cyclin-dependent kinase inhibitor (Cip1). 924 59

Blood flow and the tractive force shear stress are important determinants of artery caliber, and reduced shear predisposes arteries to intimal thickening and atherosclerosis. The molecular basis for shear-induced changes in artery wall structure is poorly defined. A number of factors associated with normal and pathological artery wall remodeling are induced by shear stress in endothelial cell cultures. These include platelet-derived growth factor (PDGF), a potent mitogen, chemoattractant, and vasoconstrictor. To determine whether similar changes occur in vivo, we examined the effects of reduced blood flow on endothelial cell PDGF expression and proliferation in the rat carotid artery. Branches of the right internal and external carotid arteries were ligated, reducing common carotid artery blood flow from 8.0+/-0.6 to 0.5+/-0.1 mL/min while increasing flow in the left carotid from 7.1+/-0.6 to 10.8+/-0.7 mL/min. Shear stress following the procedure was 1.4+/-0.2 and 33.4+/-1.1 dyne/cm2 in carotids with reduced blood flow (RF) and increased blood flow (IF), respectively. Arteries were harvested 6, 24, 48, or 72 hours after ligation, perfusion-fixed, and opened longitudinally. Endothelial cell proliferation (bromodeoxyuridine [BrdU] labeling) was assessed en face at 24, 48, and 72 hours; expression of mRNA for PDGF-A and -B chains and PDGF alpha- and beta-receptors (in situ hybridization) was determined at 6, 48, and 72 hours after unilateral flow reduction. RF induced endothelial cell proliferation, which peaked at 48 hours (RF BrdU labeling: 24 hours, 0.4+/-0.2%; 48 hours, 7.2+/-2.0%; and 72 hours, 4.1+/-0.6%; n=5). PDGF-B expression increased in RF compared with IF endothelium within 48 hours and persisted at 72 hours (percent labeling [RF/IFx100]: 6 hours, 76+/-20%; 48 hours, 395+/-179%; and 72 hours, 208+/-44%; n=3). PDGF-A expression was similarly increased in RF endothelium. In contrast, expression of PDGF alpha- and beta-receptors was undetectable in RF and IF endothelium at all times. We conclude that endothelial cell PDGF ligand expression is induced by reduced shear stress in vivo and may play an important role in flow-mediated remodeling and atherogenesis.
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PMID:Platelet-derived growth factor ligand and receptor expression in response to altered blood flow in vivo. 928 33

1. Homocysteine is an independent risk factor for cardiovascular disease. The mechanisms by which elevated plasma concentrations of homocysteine are related to the pathogenesis of atherosclerosis are not fully understood. Therefore, we examined the effect of homocysteine on cell replication of rat cultured vascular smooth muscle cells (VSMCs) at concentrations similar to those observed in clinical studies. 2. The incorporation of [3H]-thymidine was used as a marker of mitosis. Homocysteine (250-500 microM) was a weak mitogen as compared to platelet-derived growth factor-BB (PDGF-BB, 1 nM) and serum (10%), but it potentiated the mitogenic effect of PDGF-BB four fold at 500 microM. This enhancement of mitogenesis was blunted by the addition of the scavenging enzyme catalase or the antioxidant N-acetyl-L-cysteine. 3. Furthermore, stimulation of VSMC with homocysteine (25-500 microM) decreased the glutathione peroxidase activity of the cells to 50% of control at 500 microM. Inversely, homocysteine enhanced the superoxide dismutase (SOD) activity to 137% of control at 500 microM, but it had no effect on the catalase activity. 4. Homocysteine decreased the activity of bovine purified liver cytosolic glutathione peroxidase in a time- and dose-dependent manner. The maximum decrease was 50%. 5. In summary, homocysteine has a weak mitogenic effect on VSMC, but it dramatically enhances the mitogenic response of PDGF-BB, presumably by disturbing the activity of antioxidant enzymes.
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PMID:Homocysteine as a modulator of platelet-derived growth factor action in vascular smooth muscle cells: a possible role for hydrogen peroxide. 931 35

PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and soluble analog of a series of small molecules originally identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth factor receptor-1, epidermal growth factor receptor and platelet-derived growth factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n = 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD 166285 also demonstrated inhibitory activity against mitogen-activated protein kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs) and A431 cells, respectively, and basic fibroblast growth factor-mediated tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and 97.3 nM, respectively, further establishing a tyrosine kinase mechanism of inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD 166285 was long lasting and persisted for 4 days after a single 1-hr exposure followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional assays of cell attachment, migration and proliferation, in which vascular cell adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD 166285 uniquely demonstrated potent inhibition of phorbol ester-induced production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight the biological characteristics of PD 166285 as a broadly active protein tyrosine kinase capable of potently inhibiting a number of kinase mediated cellular functions, including cell attachment, movement and replication. The potential therapeutic utility of this broadly acting inhibitor as an antiproliferative and antimigratory agent could extend to such diseases as cancer, atherosclerosis and restenosis, in which redundancies in protein kinase signaling pathways are known to exist.
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PMID:In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. 940 19

A cyclic peptide analogue of platelet-derived growth factor-BB (PDGF-BB), P1 [77IVRKK81-C-73RKIE76], has recently been shown to inhibit specifically [125I]PDGF-BB/receptor binding, and PDGF-BB-induced DNA synthesis in cells expressing PDGF receptors. Here we demonstrate that P1 induces apoptosis in exponentially growing human fibroblasts as confirmed by characteristic changes in cell and nuclear morphology, by TUNEL staining and by flow cytometry. Following incubation with P1 (100 microM), the percentage of cells exhibiting DNA fragmentation increased from 24% after 8 h to 76% after 28 h as exponentially growing cells progressed through the cell cycle. We conclude from these findings taken together that apoptosis accounts for the major proportion of P1-induced cell death. Omission of the Cys residue from P1 or replacement by Ser did not alter the potency of the peptide confirming that peptide dimerisation is not important for its activity. PDGF-BB, EGF, FGF, thrombin and foetal bovine serum were not able to rescue cells from the effects of P1. P1 is a useful tool for investigation of the balance of cellular proliferation/apoptosis in wound healing, atherosclerosis and restenosis, and constitutes a basis from which to design compounds with greater potency.
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PMID:A cyclic peptide analogue of loop III of PDGF-BB causes apoptosis in human fibroblasts. 942 27

The accumulation of proteoglycans (PGs) in atherosclerosis contributes to disease progression and stenosis and may partly depend on local regulation by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta. In this study, the distribution of the major extracellular PGs is compared with that of PDGF and TGF-beta isoforms in developing lesions of atherosclerosis from hypercholesterolemic nonhuman primates. Strong immunostaining for decorin, biglycan, versican, and hyaluronan is observed in both intermediate and advanced lesions. Perlecan staining is weak in intermediate lesions but strong in advanced lesions in areas bordering the plaque core. Immunostaining for PDGF-B and TGF-beta1 is particularly prominent in macrophages in intermediate and advanced lesions. In contrast, TGF-beta2 and TGF-beta3 and PDGF-A are present in both macrophages and smooth muscle cells. Overall, PG deposits parallel areas of intense growth factor immunostaining, with trends in relative localization that suggest interrelationships among certain PGs and growth factors. Notably, decorin and TGF-beta1 are distributed similarly, predominantly in the macrophage-rich core, whereas biglycan is prominent in the smooth muscle cell matrix adjoining TGF-beta1-positive macrophages. Versican and hyaluronan are enriched in the extracellular matrix adjacent to both PDGF- and TGF-beta1-positive cells. These data demonstrate that PG accumulation varies with lesion severity, structural characteristics, and the proximity of PDGF and TGF-beta.
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PMID:Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. 946 80


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