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)

Tissue factor (TF), a transmembrane glycoprotein, initiates the extrinsic coagulation cascade. TF is known to play a major role in mediating thrombosis and thrombotic episodes associated with the progression of atherosclerosis. Macrophages at inflammatory sites, such as atherosclerotic lesions, release numerous cytokines that are capable of modulating TF expression. This study examined the role of oncostatin M (OSM), a macrophage/ T-lymphocyte-restricted cytokine, in the expression of TF in vascular smooth muscle cells (SMCs). It is reported here that OSM stimulated a biphasic and sustained pattern of TF messenger RNA (mRNA). The effect of OSM on TF mRNA expression was regulated at the transcriptional level as determined by nuclear run-offs and transient transfection of a TF promoter-reporter gene construct. OSM-induced TF expression was regulated primarily by the transcription factor NF-kappaB. Activation of NF-kappaB by OSM did not require IkappaB-alpha degradation. Inhibition of MEK activity by U0126 prevented OSM-induced TF expression by suppressing NF-kappaB DNA binding activity as determined by gel-shift analysis. Further, inhibition of Erk-1/2 protein by antisense treatment resulted in suppression of TF mRNA expression, indicating a role for Erk-1/2 in modulating NF-kappaB DNA binding activity. These studies suggest that the induced expression of TF by OSM is primarily through the activation of NF-kappaB and that activation of NF-kappaB is regulated in part by the MEK/Erk-1/2 signal transduction pathway. This study indicates that OSM may play a key role in promoting TF expression in SMCs within atherosclerotic lesions.
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PMID:Oncostatin M promotes biphasic tissue factor expression in smooth muscle cells: evidence for Erk-1/2 activation. 1115 86

The influence of thyroid failure on haemostasis is controversial, both hypocoagulable and hypercoagulable states have been reported. Since both subclinical and overt hypothyroidism have been associated with atherosclerosis, a hypercoagulable state in addition might represent a risk factor for thromboembolic disease. We investigated various haemostatic variables in 42 women with subclinical hypothyroidism and compared them to 66 euthyroid controls. Prothrombin time, activated partial thromboplastin time, fibrinogen, factor VII activity (FVII:C), factor VII antigen (FVII:Ag), factor VIII activity, von Willebrand factor (vWF), antithrombin III, heparin cofactor II, protein C, protein S, plasminogen, antiplasmin, plasminogen activator inhibitor and tissue plasminogen activator, as well as common lipid variables, were measured. Factor VII:C (P < 0.02) and the ratio FVII:C/FVII:Ag (P < 0.01) were significantly increased in subclinical hypothyroid patients compared to the control group. Both parameters remained higher in hypothyroid patients after exclusion of 18 women on oestrogen replacement therapy. No differences were found between the groups with respect to vWF or the other haemostatic and lipid variables tested. Patients with subclinical hypothyroidism had significantly higher levels of FVII:C. The greater increase in FVII:C compared to that of FVII:Ag, as shown by the increase in their ratio, might reflect the presence of activated FVIIa. This might mean a hypercoagulable state, which could contribute to the increased prevalence of coronary heart disease reported in such patients. A hypercoagulable state might be another argument in favour of thyroxine replacement treatment in subclinical hypothyroidism, especially in patients with additional risk factors for vascular disease.
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PMID:Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease. 1116 51

The importance of low-density lipoprotein (LDL) in the etiology of atherosclerosis is well recognized. We have established a reproducible stenosis model in hypercholesterolemic hamsters, and the process of arterial stenosis by thrombus or neointima was studied and compared with that in normal hamsters. The level of plasma LDL was 4.6 times higher in hamsters fed a high-cholesterol diet than in hamsters fed normal food. Endothelial injury in right common carotid arteries was induced using a modified catheter. Arterial blood flow was monitored continuously using a Doppler flow probe. Arterial patency after the initiation of injury in high-cholesterol hamsters was significantly changed as compared with that of normal hamsters. Neointima was observed 2 wk after the vascular injury. The neointimal area of high-cholesterol hamsters was significantly larger than that of normal hamsters. To characterize the stenosis in hypercholesterolemic hamsters, we measured platelet aggregation, thrombin time, activated partial thromboplastin time, and proliferating smooth muscle cells (SMC) in vitro and in vivo. The half-maximal inhibitory concentration value for platelet aggregation induced by thrombin or collagen, the DNA synthesis stimulated by platelet-derived growth factor (PDGF)-BB, and 5-bromo-2-deoxy-uridine labeling indices (proliferating index of SMC in vivo) in high-cholesterol hamsters were each significantly higher than the comparable value from normal hamsters. However, specific binding of PDGF-BB in SMC was not different between the two types of hamsters. Furthermore, we investigated the inhibitory effects of probucol or losartan on neointima formation using this model. Probucol, but not losartan, significantly reduced the neointimal area in hypercholesterolemic hamsters. These findings indicated that high levels of plasma LDL strongly contributed to the development of thrombus and neointima formation via both up-regulation of platelet aggregation and the enhancement of SMC proliferation. This stenosis model may be useful for the investigation of hypercholesterolemia-associated cardiovascular diseases.
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PMID:Characterization of simple and reproducible vascular stenosis model in hypercholesterolemic hamsters. 1143 56

Hemodynamic forces play a critical role in the pathogenesis of atherosclerosis as evidenced by the focal nature of the disease. Oscillatory shear stress characterizes the hemodynamic environment of plaque-prone areas as opposed to unidirectional shear stress typical of plaque-free areas. These particular flow conditions modulate atherosclerosis-related genes. Tissue factor (TF) initiates blood coagulation, contributes to vascular remodeling, and is therefore a potential contributor in the development/progression of atherosclerosis. We investigated the effect of oscillatory and unidirectional flows on TF using an in vitro perfusion system. Human endothelial cells exposed for 24 h to oscillatory shear stress, significantly increased TF mRNA, and TF protein expression (1.5- and 1.75-fold, respectively, p < 0.01), and surface TF activity (twofolds-increase). Expression of TF inhibitor (TFPI), mRNA and protein, remained unchanged as compared to static conditions. Conversely, cells exposed to unidirectional shear, showed a decrease in TF activity with a significant increase in TFPI mRNA and protein expression (1.5- and 1.8-fold, respectively, p < 0.01). These results show for the first time that pulsatile oscillatory shear stress induces a pro-coagulant phenotype of endothelial cells which may favor formation/progression of atherothrombotic lesions.
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PMID:Tissue factor activity is upregulated in human endothelial cells exposed to oscillatory shear stress. 1208 87

Restenosis is responsible to approximately 30% of long-term failure following therapeutic vascular procedures. Thrombosis plays a key role in the development of restenosis. Thrombin-specific inhibitors have been considered as one type of candidates for the prevention of restenosis. Previous studies by our group demonstrated that a novel thrombin-specific inhibitor, hirulog-like peptide (HLP), reduced balloon catheter-induced neointima formation in rat carotid arteries. The present study examined the effect of HLP on angioplasty-induced restenosis in carotid arteries of atherosclerotic rabbits. New Zealand white rabbits were subject to air desiccation of the lumen of the right carotid arteries, then received high cholesterol/fat diet for 3 weeks. The rabbits were intravenously infused with HLP (1.6 mg/(kg/h)) or saline (n=7 per group) for 4 h started before angioplasty which dilated atherosclerotic lesions in right common carotid artery. Four weeks after the angioplasty, neointimal area, stenosis and neointima/media ratio in injured carotid arteries were reduced in atherosclerotic rabbits treated with HLP compared to saline controls by 62, 39 and 59% (P<0.05). The expression of tissue factor (TF) and transforming growth factor (TGF)-beta in the neointima of carotid arteries of rabbits treated with HLP was significantly weaker than saline controls (P<0.05 or <0.01). Activated partial thromboplastin time and bleeding time in HLP-treated rabbits were not significantly prolonged compared to controls. The results of the present study suggest that HLP may substantially reduce angioplasty-induced restenosis in atherosclerotic rabbits without increasing bleeding tendency. The inhibition on the expression of TF and TGF-beta in the neointima of the arterial wall may contribute to the preventive effect of HLP on restenosis in atherosclerotic rabbits.
Atherosclerosis 2003 Jul
PMID:Hirulog-like peptide reduces restenosis and expression of tissue factor and transforming growth factor-beta in carotid artery of atherosclerotic rabbits. 1286 Feb 48

We investigated the effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E) on blood coagulation abnormalities and dysfunction of vascular endothelial cells in spontaneously diabetic Otsuka Long-Evans Tokushima Fatty rats. The animals were treated with either EPA-E or lard at a daily dose of 0.3 g/kg/day for 52 weeks by gavage, and their coagulation/fibrinolytic parameters, platelet aggregation, and functions of the vascular endothelial cells were examined. EPA-E significantly improved coagulation-related parameters including prothrombin time, activated partial thromboplastin time, fibrinogen level, and activities of factor II, V, VII, VIII, IX, X, XI, and XII, and antithrombin III, and fibrinolysis-related parameters including plasminogen, tissue-type plasminogen activator, alpha(2)-plasmin inhibitor, and plasminogen activator inhibitor. It also suppressed ADP- or collagen-induced platelet aggregation and the cholesterol/phospholipid molar ratio in platelet membranes at a dose of 0.3 g/kg. In addition, it significantly increased the migration activity of vascular endothelial cells, and decreased the binding of vascular endothelial cells to vascular endothelial growth factor. In contrast, lard had no effect on hypercoagulation, hypofibrinolysis, and platelet hyperaggregation but significantly aggravated the dysfunction of vascular endothelial cells. These data demonstrate that EPA-E beneficially altered certain factors known to promote thrombosis and atherosclerosis in this animal model.
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PMID:Long-term administration of highly purified eicosapentaenoic acid ethyl ester improves blood coagulation abnormalities and dysfunction of vascular endothelial cells in Otsuka Long-Evans Tokushima fatty rats. 1461 17

Activation of vascular smooth muscle cells (SMCs) by platelet-derived growth factor (PDGF) is a seminal event in the initiation and progression of the atherosclerotic lesion and may contribute to atherosclerotic plaque instability with plaque rupture and thrombus formation. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play a major role in thrombus formation after plaque rupture. This study examined intracellular signaling pathways leading to TF expression and Egr-1 activation, a key element in tissue factor transcription, by PDGF-BB in rat SMCs. PDGF-BB induced TF mRNA and protein expression in a time-dependent manner. Early growth response factor-1 (Egr-1) binding activity was also induced by PDGF-BB, as well as phosphorylation of extracellular signal-regulated kinase. PDGF-BB-induced Egr-1 activation was suppressed by inhibitors of 2 upstream activators of Egr-1, extracellular signal-regulated kinase (ERK) and Src family kinases, whereas antioxidants, phosphatidylinositol 3-phosphate kinase, and p38 MAPK inhibitors had no effect. PDGF-BB-stimulated expression of the transcriptional co-repressor NAB2 was time-dependent. Furthermore, transient transfections of SMCs with wild-type and mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of PDGF-BB-induced TF expression. Taken together, the results suggest that PDGF-BB induces TF expression and activity in SMC by a Src family kinases/ERK/Egr-1 signaling pathway and may therefore contribute to thrombus formation in advanced atherosclerosis and restenosis.
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PMID:Platelet-derived growth factor induces tissue factor expression in vascular smooth muscle cells via activation of Egr-1. 1549 29

Although anticardiolipin antibody (aCL) has been suggested to be a potent risk factor for thrombosis and atherosclerosis in multiple arterial beds, conflicting results still exist between aCL and cerebral ischemia in the general stroke population. To elucidate if this discrepancy relates to the heterogeneity of underlying etiologies, blood beta(2)-glycoprotein I dependent-aCL was evaluated in 432 Taiwanese adults associated with cerebral ischemia who were classified into five subtypes according to their causes of cerebral ischemia. The results were compared with those in 100 healthy controls. A definite increase of aCL-IgG isotype was found in 41 patients (9.35%) and four controls (4.0%). The relative risk was 2.52. The frequency of increased aCL-IgG was 12.2%, 12.8%, 8.8%, 3.9%, and 3.5% in patients with large-artery atherosclerotic disease, stroke of unknown etiology, small-artery occlusive disease, cardioembolism, and stroke of other known etiology, respectively. Only patient with large-artery atherosclerotic disease (p<0.025) and stroke of unknown etiology (p<0.05) had a higher frequency of increased aCL than control. The frequencies of abnormal result of activated partial thromboplastin time, antinuclear factor, Coombs' test, and venereal disease research laboratory were 2.84%, 1.22%, 1.02%, and 1.34% in these 41 patients, respectively. Accordingly, aCL-IgG selectively increases in patients with large-artery atherosclerosis and stroke of unknown etiology, reflecting selective activation of humoral immunity for aCL in the pathogenesis of cerebral ischemia.
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PMID:The increase of blood anticardiolipin antibody depends on the underlying etiology in cerebral ischemia. 1582 27

Oxidatively modified low-density lipoprotein (OxLDL) is present in atherosclerotic lesions and has been proposed to play an important role in atherogenesis. Thrombosis is the major mechanism underlying acute complications of atherosclerosis. In the present study, we analyzed the interaction between OxLDL and blood coagulation factors, which are involved in the blood coagulation pathway. We investigated the effect of OxLDL on plasma coagulation by measuring prothrombin time (PT) as a parameter of the extrinsic pathway of blood coagulation and activated partial thromboplastin time (APTT) as a parameter of the intrinsic pathway of blood coagulation following the addition of OxLDL to plasma. OxLDL, but not native LDL, caused prolongation of APTT in a dose- and oxidation time-dependent manner. In addition, the oxidatively modified product of acetylated LDL (AcLDL), but not AcLDL, also caused prolongation of APTT. The inhibition of lysophosphatidylcholine production in OxLDL by phenylmethylsulfonyl fluoride or Pefabloc pretreatment of LDL resulted in a prolongation of APTT, which was equivalent to the effect of OxLDL. Moreover, OxLDL significantly inhibited blood coagulation factor VIII, IX, and XI activity. Furthermore, we demonstrated that recombinant factor VIII binds to OxLDL and that factor VIII associated with OxLDL is detected in the incubation mixture of OxLDL and plasma. These results indicate that the binding of factor VIII to OxLDL affects the intrinsic pathway of the blood coagulation cascade. The present study suggests that the interaction between OxLDL and factor VIII may provide important information on the initiation and progression of atherosclerosis.
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PMID:Inhibition of plasma coagulation through interaction between oxidized low-density lipoprotein and blood coagulation factor VIII. 1593 Jul 25

Atherosclerosis is considered to be an inflammatory disease. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play an essential role in thrombus formation after atherosclerotic plaque rupture. Recent studies suggest that the antiinflammatory cytokine interleukin-10 (IL-10) has many antiatherosclerotic properties. Therefore, the effects of IL-10 on TF expression in response to inflammation were investigated. Mouse macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of IL-10. Pretreatment with IL-10 resulted in a 50% decrease in TF mRNA expression and TF promoter activity. Binding of early growth response gene-1 (Egr-1) to the consensus DNA sequence, a key transcriptional activator of TF expression in response to inflammation, and the expression of Egr-1 mRNA were also inhibited by IL-10. This inhibition was independent of the induction of suppressor of cytokine signaling protein-3 by IL-10. Macrophages that had been transfected with luciferase reporter constructs containing the murine Egr-1 5'-flanking sequence exhibited reduced reporter gene activity in response to LPS stimulation with IL-10 pretreatment. Studies with deletion constructs of the Egr-1 promoter identified the proximal serum response element SRE3 as a potential regulatory site for the IL-10 mediated suppression of Egr-1 expression. Furthermore, activation of the upstream signal-transduction elements, such as mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase 1/2, and Elk-1 were also inhibited by IL-10 pretreatment. Taken together, these results demonstrate a pathway for the IL-10 mediated inhibition of TF expression during inflammation and may explain the antiatherosclerotic effects of IL-10.
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PMID:Interleukin-10 suppresses tissue factor expression in lipopolysaccharide-stimulated macrophages via inhibition of Egr-1 and a serum response element/MEK-ERK1/2 pathway. 1603 70


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