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)

Thrombin is a serine protease involved in haemostasis which exerts a number of cellular effects, including stimulating mesenchymal cell migration, proliferation, and has been implicated both in normal wound healing and pathological conditions associated with hyperproliferation of smooth muscle cells such as atherosclerosis and restenosis. We hypothesize that thrombin, in addition to its proliferative effects, may also influence the deposition of matrix proteins at sites of vascular injury by directly stimulating smooth muscle cell procollagen production. 10 nM thrombin significantly stimulated rat aortic smooth muscle cell procollagen production by 34 +/- 3% compared to media control cells over a 48 h incubation period, and increased steady state alpha1(I) procollagen mRNA levels by up to 104 +/- 22%. These effects are mediated via interaction of thrombin with the PAR-1 receptor since TRAP (Thrombin Receptor Activating Peptide) stimulated procollagen production by 23 +/- 0.5%. In addition, conditioned medium from thrombin-treated cells stimulated procollagen production by 30 +/- 3% suggesting that thrombin is acting via the production and/or release of an autocrine mediator. These data suggest a novel role for thrombin in vascular wound healing and the development of pathological conditions associated with increased connective tissue deposition.
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PMID:Thrombin stimulates smooth muscle cell procollagen synthesis and mRNA levels via a PAR-1 mediated mechanism. 949 99

In addition to its pivotal role in hemostasis, thrombin activates various cell types such as platelets and vascular smooth muscle cells via proteolytic processing of specific cell-surface receptors known as proteinase activated receptors (PARs), the prototype of which is PAR-1. Thrombin receptor activation is likely to play a key role in cardiovascular disorders such as arterial thrombosis, atherosclerosis and restenosis, and as such a thrombin receptor antagonist should have potential utility in the treatment of these disorders. Since the fibrin pathway is unaffected by thrombin receptor antagonism, a thrombin receptor antagonist is expected to have minimal bleeding liability, which is a complicating factor in existing antithrombotic therapy. The currently available collection of thrombin receptor antagonists fall into three categories: (i) peptide antagonists; (ii) peptidomimetics; and (iii) non-peptide thrombin receptor antagonists, and this review outlines the development of members of these classes.
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PMID:Thrombin receptor antagonists as novel therapeutic targets. 1172 7

Proliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the key events in the pathogenesis of atherosclerosis and restenosis. We investigated whether YD-3, a lowmolecular weight, non-peptide compound, could modulate proliferation of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD-3 on thrombininduced VSMC proliferation by [(3)H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation in a concentration-dependent manner. To define the mechanisms of YD-3 action, we found that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities by using Western blotting analysis. Furthermore, oral administration of YD-3 exhibited a marked reduction in neointimal thickness using the carotid injury model in rats. Using immunochemical detection, our experiments also revealed that YD-3 significantly suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1-activating peptide (SFLLRN)-induced VSMC proliferation in a concentration-dependent manner. These results suggest that YD-3 inhibits thrombin-induced VSMC growth via the Ras- and ERK1/2-mediated signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment of atherosclerosis and restenosis after vascular injury.
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PMID:The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury. 1558 28

Endothelial membrane-bound thrombomodulin is a high affinity receptor for thrombin to inhibit coagulation. We previously demonstrated that the thrombin-thrombomodulin complex restrains cell proliferation mediated through protease-activated receptor (PAR)-1. We have now tested the hypothesis that thrombomodulin transduces a signal to activate the endothelial nitric-oxide synthase (NOS3) and to modulate G protein-coupled receptor signaling. Cultured human umbilical vein endothelial cells were stimulated with thrombin or a mutant of thrombin that binds to thrombomodulin and has no catalytic activity on PAR-1. Thrombin and its mutant dose dependently activated NO release at cell surface. Pretreatment with anti-thrombomodulin antibody suppressed NO response to the mutant and to low thrombin concentration and reduced by half response to high concentration. Thrombin receptor-activating peptide that only activates PAR-1 and high thrombin concentration induced marked biphasic Ca2+ signals with rapid phosphorylation of PLC(beta3) and NOS3 at both serine 1177 and threonine 495. The mutant thrombin evoked a Ca2+ spark and progressive phosphorylation of Src family kinases at tyrosine 416 and NOS3 only at threonine 495. It activated rapid phosphatidylinositol-3 kinase-dependent NO synthesis and phosphorylation of epidermal growth factor receptor and calmodulin kinase II. Complete epidermal growth factor receptor inhibition only partly reduced the activation of phospholipase Cgamma1 and NOS3. Prestimulation of thrombomodulin did not affect NO release but reduced Ca2+ responses to thrombin and histamine, suggesting cross-talks between thrombomodulin and G protein-coupled receptors. This is the first demonstration of an outside-in signal mediated by the cell surface thrombomodulin receptor to activate NOS3 through tyrosine kinase-dependent pathway. This signaling may contribute to thrombomodulin function in thrombosis, inflammation, and atherosclerosis.
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PMID:Endothelial thrombomodulin induces Ca2+ signals and nitric oxide synthesis through epidermal growth factor receptor kinase and calmodulin kinase II. 1612 27

Leukocyte recruitment and the expression of pro-inflammatory cytokines are prevalent characteristics of early atherogenesis. Recently, several inflammatory mediators have been linked to atheroma formation and inflammatory pathways have been shown to promote thrombosis. The discovery of mast cells, activated T lymphocytes and macrophages in atherosclerotic lesions, the detection of human leukocyte antigen class II expression, and the finding of local secretion of several cytokines all suggest the involvement of immune and inflammatory mechanisms in the pathogenesis of atherosclerosis. Recent research suggests activation of protease activated receptors (PAR) on the surface of endothelial cells may play a role in general mechanisms of inflammation. In previous studies, our laboratory has demonstrated that thrombin (which activates PAR-1) and tryptase (which activates PAR-2) stimulation of endothelial cells results in activation of calcium-independent phospholipase A(2) (iPLA(2)). iPLA(2) plays a critical role in the synthesis of membrane phospholipid-derived inflammatory mediators such as arachidonic acid, platelet activating factor (PAF), and prostaglandins, all demonstrated to be central in both the initiation and propagation of the inflammatory response. Activation of iPLA(2) results in release of choline lysophospholipids from endothelial cells, these metabolites may contribute to the initiation of ventricular arrhythmias following myocardial ischemia as a direct result of incorporation into the myocyte sarcolemma. This biochemical event represents a direct link between occlusion of a coronary vessel and the nearly immediate initiation of arrhythmogenesis often seen in myocardial ischemia.
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PMID:The therapeutic potential of phospholipase A2 inhibitors in cardiovascular disease. 1726 51

Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCII deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII(-/-) mice were embryonically lethal. In HCII(+/-) mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-1-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII(+/-) mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII(+/-) mice. The intimal hyperplasia in HCII(+/-) mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.
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PMID:Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice. 1754 53

Oxidation-sensitive signals play an important role in platelet activation. AGI-1067 is a novel, phenolic, intra- and extracellular antioxidant that inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. AGI-1067 is the metabolically stable monosuccinic acid ester of probucol, and a potent phenolic antioxidant representing a novel class of orally bioavailable compounds termed vascular protectants. AGI-1067 exhibits antioxidant activity equipotent to probucol. In addition, animal studies have demonstrated dual pharmacological activities of AGI-1067: the ability to block the expression of oxidation-sensitive inflammatory genes including genes that code for vascular cell adhesion molecule-1 and monocyte chemotactic protein-1. Importantly, AGI-1067 also exhibits mild antiplatelet properties inhibiting surface expression of various key platelet receptors, the formation of platelet monocyte microparticles and PAR-1 thrombin receptors. AGI-1067 is currently being tested in the late trials, and if proven to improve clinical outcomes (ARISE trial), the drug will ultimately be used in patients with different manifestations of atherosclerosis and atherothrombosis.
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PMID:AGI-1067, a novel vascular protectant, anti-inflammatory drug and mild antiplatelet agent for treatment of atherosclerosis. 1760 42

Thrombin is a potent stimulant of smooth muscle cell (SMC) proliferation in inflammatory conditions, leading to pathological thickening of vascular walls in atherosclerosis and airway remodeling in asthma. Cell proliferation requires the formation and remodeling of cell membrane phospholipids (PLs), involving the activation of PL-metabolizing enzymes. Yet, the role of specific PL-metabolizing enzymes in SMC proliferation has hardly been studied. To bridge this gap, in the present study, we investigated the role of key enzymes involved in PL metabolism, the PL-hydrolyzing enzyme phospholipase A2 (PLA2) and the PL-synthesizing enzyme lysophosphatidic acid-fatty acid transacylase (LPAAT), in thrombin-induced proliferation of bovine aortic SMCs (BASMCs). Concomitantly with the induction of BASMC proliferation, thrombin activated cytosolic PLA2 (cPLA2-alpha), expressed by selective release of arachidonic acid and mRNA expression, as well as LPAAT, expressed by nonselective incorporation of fatty acid and mRNA expression. Specific inhibitors of these enzymes, arachidonyl-trifluoromethyl-ketone for cPLA2 and thimerosal for LPAAT, suppressed their activities, concomitantly with suppression of BASMC proliferation, suggesting a mandatory requirement for cPLA2 and LPAAT activation in thrombin-induced SMC proliferation. Thrombin acts through the protease-activated receptor (PAR-1), and, accordingly, we found that thrombin-induced BASMC proliferation was suppressed by the PAR-1 inhibitor SCH-79797. However, the PAR-1 inhibitor did not prevent thrombin-induced mRNA expression of cPLA2 and LPAAT, implying that the activation of cPLA2 and LPAAT is essential but not sufficient for thrombin-induced proliferation of BASMCs.
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PMID:Activation of cytosolic phospholipase A2 and fatty acid transacylase is essential but not sufficient for thrombin-induced smooth muscle cell proliferation. 1838 89

There is accumulating evidence that activation of sphingosine kinase 1 (SPHK1) is an important element in intracellular signalling cascades initiated by stimulation of multiple receptors, including certain growth factor, cytokine, and also G-protein coupled receptors. We here report that stimulation of the lung epithelial cell line A549 by thrombin leads to transient increase of SPHK1 activity and elevation of intracellular sphingosine-1-phosphate (S1P); abrogation of this stimulation by SPHK1-specific siRNA, pharmacological inhibition, or expression of a dominant-negative SPHK1 mutant blocks the response to thrombin, as measured by secretion of MCP-1, IL-6, IL-8, and PGE(2). Using selective stimulation of proteinase-activated receptors (PARs) a specific involvement of SPHK1 in the PAR-1 induced responses in A549 cell, including activation of NFkappaB, was evident, while PAR-2 and PAR-4 responses were independent of SPHK1. Moreover, PAR-1 or thrombin-induced cytokine production and adhesion factor expression of human umbilical vein endothelial cells was also seen to depend on SPHK1. Using dermal microvascular endothelial cells from SPHK1-deficient mice, we showed that absence of the enzyme abrogates MCP-1 production induced in these cells upon treatment with thrombin or PAR-1 activating peptide. We propose SPHK1 inhibition as a novel way to block PAR-1 mediated signalling, which could be useful in treatment of a number of diseases, in particular in atherosclerosis.
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PMID:Sphingosine kinase 1 is essential for proteinase-activated receptor-1 signalling in epithelial and endothelial cells. 1916 17

Macrophages as inflammatory cells are involved in the pathogenesis of atherosclerosis that today is recognized as an inflammatory disease. Activation of coagulation leads to the late complication of atherosclerosis, namely atherothrombosis with its clinical manifestations stroke, unstable angina, myocardial infarction, and sudden cardiac death. Thus inflammation and coagulation play fundamental roles in the pathogenesis of atherosclerosis. We show that the coagulation enzyme thrombin up-regulates oncostatin M (OSM), a pleiotropic cytokine implicated in the pathophysiology of vascular disease, in human monocyte-derived macrophages (MDMs) up to 16.8-fold. A similar effect was seen in human peripheral blood monocytes and human plaque macrophages. In MDMs, the effect of thrombin on OSM was abolished by PPACK and mimicked by a PAR-1-specific peptide. Thrombin induced phosphorylation of ERK1/2 and p38 in MDMs. The ERK1/2 inhibitor PD98059 blocked the effect of thrombin on OSM production in MDMs, whereas the p38 inhibitor SB202190 had no effect. Thrombin induced translocation of c-fos and c-jun to the nucleus of MDMs. Using OSM promoter-luciferase reporter constructs transfected into MDMs, we show that a functional AP-1 site is required for promoter activation by thrombin. We present another link between coagulation and inflammation, which could impact on the pathogenesis of atherosclerosis.
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PMID:Thrombin induces the expression of oncostatin M via AP-1 activation in human macrophages: a link between coagulation and inflammation. 1965


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