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)

Phenotypic modulation of vascular smooth muscle cell plays a pivotal role in the development of vascular pathology, such as atherosclerosis and restenosis after angioplasty. We have identified the zinc finger protein BTEB2 as a DNA binding protein that regulates the nonmuscle myosin heavy chain (SMemb) promoter. BTEB2 is expressed in fetal aorta but not in adult aorta and is induced in the neointima in response to vascular injury. BTEB2 also activates a number of vascular disease-associated genes, such as tissue factor, PAI-1 (plasminogen activator inhibitor-1), and Egr-1 gene. We have further isolated and characterized the human BTEB2 gene. Functional studies using 5'-deletion and site-directed mutation constructs demonstrated that phorbol ester induces Egr-1, which can activate the BTEB2 promoter through binding to -32 from the transcription start site. These results suggest that phenotypic modulation of vascular smooth muscle cells occurring in response to mitogen stimulation may be mediated by BTEB2 through Egr-1 induction.
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PMID:Transcriptional regulation of smooth muscle phenotypic modulation. 1086 41

Accelerated coronary atherosclerosis in cardiac allografts is a major factor limiting survival after heart transplantation, and activation of the coagulation system contributes to accelerated transplant atherosclerosis. Accordingly, increased tissue factor (TF) expression by monocyte/macrophages may play a pivotal role underlying deposition of fibrin in the affected vessels. To evaluate the potential effects of an important immunosuppressive agent, tacrolimus hydrate (FK-506), on monocyte/macrophages and their response to lipopolysaccharide (LPS), we exposed human monocyte/macrophage cell line (THP-1 cells), to LPS and characterized its procoagulant activity (PCA). FK-506 exerted a concentration-dependent inhibitory effect on LPS (10 micrograms/ml) induction of procoagulant activity, identified as TF activity as judged from immunostaining of TF antigen and by functional characterization with the use of coagulation factor VII-deficient plasma and an antibody against human TF. In addition, the reverse transcription polymerase chain reaction demonstrated reduced expression of TF mRNA in LPS-stimulated THP-1 cells exposed to FK-506. Thus, FK-506 acts favorably not only as a direct immunomodulating agent but also as an alleviator of local activation of the coagulation cascade contributing to transplant arteriopathy through modulation of monocyte expression of TF.
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PMID:Effects of tacrolimus hydrate (FK-506) on the expression of tissue factor in THP-1 human monocyte cell line. 1088 73

Moderately elevated plasma homocysteine levels are an important independent risk factor for arterial and venous thrombosis and for atherosclerosis. Some investigators have proposed that homocysteine's effects result from oxidant injury to the vascular endothelium or from an alteration in endothelial function. However, homocysteine may have other cellular targets. We now report that homocysteine, at physiologically relevant concentrations, induces the expression of tissue factor by monocytes. In response to homocysteine, monocytes express procoagulant activity in a dose-dependent and a time-dependent manner. This activity is attributable to tissue factor because it was dependent on factor VII and blocked by anti-tissue factor antibodies. Tissue factor mRNA levels were also increased in monocytes after homocysteine treatment. The effect was found to be specific because analogues of homocysteine (homocystine and homocysteine thiolactone) did not mimic homocysteine's activity, nor did other thiol compounds (cysteine, 2-mercaptoethanol, dithiothreitol). On the other hand, methionine, the metabolic precursor of homocysteine, was active though less potent than homocysteine. Catalase and superoxide dismutase (scavengers of H(2)O(2) and O(2)(-) Radicals, respectively) were unable to block the expression of tissue factor induced by homocysteine, as was a 5-fold excess of the reducing agent 2-mercaptoethanol. We conclude that the induction of tissue factor expression by circulating monocytes is a plausible mechanism by which homocysteine may induce thrombosis and that a nonspecific redox process is not involved.
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PMID:Induction of monocyte tissue factor expression by homocysteine: a possible mechanism for thrombosis. 1091 Sep 11

Homocysteine is a non-protein-forming sulphur amino acid that plays an important role in remethylation and trans-sulphuration processes. In recent years, a high plasma homocysteine concentration has been implied as a possible pathophysiological factor in atherosclerosis and artery and deep vein thrombosis, probably through generation of H(2)O(2), enhanced platelet activity and increased production of macrophage-derived tissue factor. Furthermore, an increase of polymorphonuclear leukocyte (PMN) activity mediated by homocysteine-generated H(2)O(2) has also been reported. Because some preliminary experimental results in our laboratory did not confirm this effect of homocysteine on PMNs, we investigated the effect of homocysteine on the activity of PMNs, measured by their luminol-dependent chemiluminescence. Moreover, we also studied the effect of homocysteine in a luminol-hypochlorite chemiluminescent system. Our results clearly indicate that homocysteine at micromol/L concentrations (10-100 micromol/L) slightly inhibits neutrophil chemiluminescence, while it strongly inhibits the luminescence of the luminol-hypochlorite system. Therefore, the hypothesis that homocysteine induces an increase of H(2)O(2)-mediated neutrophil activity is not supported and, probably, the common opinion that views the H(2)O(2) generated by homocysteine as a possible mechanism for cardiovascular damage should be reconsidered.
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PMID:Effect of homocysteine on polymorphonuclear leukocyte activity and luminol-dependent chemiluminescence. 1093 39

Tissue factor (TF) is one of the major initiators of coagulation and raised plasma levels have been found in various cardiovascular diseases. TF activity is, however, regulated by tissue factor pathway inhibitor (TFPI), and alteration in levels of TF and/or TFPI may thus relate to thrombogenesis and atherogenesis. To investigate possible abnormalities in TF and free TFPI (i.e. unbound to TF) and total TFPI among patients with peripheral artery disease (PAD), we studied 42 patients (mean age 57, 35 men) with objectively proven (by ABPI/Doppler) disease and 42 age- and sex- matched healthy controls. TF, free TFPI and total TFPI were measured in citrated plasma by ELISA. TF was higher in the patients with PAD compared to controls (275+/-122 pg/ml versus 158+/-60, P<0.0001) but levels of total TFPI were lower in the patients (43+/-10 ng/ml versus 50+/-15, P=0.021). There was no significant difference in levels of free TFPI between patients and controls (7.2+/-1.5 ng/ml in controls, 7.5+/-1. 6 among patients, P=0.39). Within the control patients, levels of free and total TFPI were significantly correlated (Spearman r=0.51, P=0.001) but in the patients with PAD this correlation was poor (r=0. 21, P=0.178). We suggest that reduced levels of total TFPI and raised levels of TF may contribute to the process of atherogenesis and the increased risk of thrombosis among patients with cardiovascular disease.
Atherosclerosis 2000 Sep
PMID:Differences in free and total tissue factor pathway inhibitor, and tissue factor in peripheral artery disease compared to healthy controls. 1099 36

The mechanism of the progression of atherosclerosis involves the rupture of a plaque with thrombus formation, followed by an invasion of monocytes that induce the formation of tissue factor and a second thrombus. This is followed by activation of the smooth muscle cells of the arterial wall with formation of connective tissue that infiltrates both thrombi. We can try to prevent atherosclerosis progression by inhibiting thrombosis with an inhibitor of tissue factor, inhibiting the process of scarring with Rapamycin, or both. Nowadays, we can study these processes using highly sensitive techniques to monitorize the formation and evolution of the thrombus, and magnetic resonance imaging that allow us to study the growth of the connective tissue. With these techniques we can study the natural history of atherosclerosis and the efficacy of different drugs to prevent its progression.
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PMID:[Thrombus remodeling. Key factor in the progression of coronary atherosclerosis]. 1100 62

There is increasing evidence for functional crosstalk between inflammatory and thrombotic pathways in inflammatory vascular diseases such as atherosclerosis and vasculitis. Thus, complement activation on the endothelial cell (EC) surface during inflammation may generate thrombin via the synthesis of tissue factor. We explored the hypothesis that thrombin induces EC expression of the complement-regulatory proteins decay-accelerating factor (DAF), membrane cofactor protein (MCP), and CD59 and that this maintains vascular integrity during coagulation associated with complement activation. Thrombin increased DAF expression on the surface of ECs by 4-fold in a dose- and time-dependent manner as measured by flow cytometry. DAF up-regulation was first detectable at 6 hours and maximal 24 hours poststimulation, whereas no up-regulation of CD59 or MCP was seen. Thrombin-induced expression required increased DAF messenger RNA and de novo protein synthesis. The response depended on activation of protease-activated receptor 1 (PAR1) and was inhibited by pharmacologic antagonists of protein kinase C (PKC), p38 and p42/44 mitogen-activated protein kinase, and nuclear factor-kappa B. The increased DAF expression was functionally relevant because it significantly reduced C3 deposition and complement-mediated EC lysis. Thus, thrombin-generated at inflammatory sites in response to complement activation-is a physiologic agonist for the PKC-dependent pathway of DAF regulation, thereby providing a negative feedback loop protecting against thrombosis in inflammation. (Blood. 2000;96:2784-2792)
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PMID:Induction of decay-accelerating factor by thrombin through a protease-activated receptor 1 and protein kinase C-dependent pathway protects vascular endothelial cells from complement-mediated injury. 1102 12

Studies in healthy subjects showed that blood coagulation factor VII (FVII) is activated postprandially after consumption of high-fat meals, but accompanying thrombin formation has not been demonstrated. In patients with coronary atherosclerosis, the arterial intima is supposed to present more tissue factor, the cofactor of FVII, to circulating blood; therefore, thrombin formation in response to FVII activation is more likely to occur in such patients. This hypothesis was tested in a randomized crossover study of 30 patients (aged 43 to 70 years) with stable angina pectoris and angiographically verified coronary atherosclerosis. They were served a low-fat (5% of energy from fat) breakfast and lunch and a high-fat (40% of energy from fat) breakfast and lunch on 2 different days. Venous blood samples were collected at 8:15 AM (fasting), 12:30 PM, 2:00 PM, 3:30 PM, and 4:45 PM and analyzed for triglycerides, activated FVII (FVIIa), FVII protein concentration (FVII:Ag), prothrombin fragment 1+2 (F1+2), and soluble fibrin. Triglyceride levels increased from fasting levels on both diets, but they increased most markedly on the high-fat diet. FVIIa and FVIIa/FVII:Ag increased with the high-fat diet and decreased with the low-fat diet. For both diets, FVII:Ag and F1+2 decreased slightly. No postprandial changes were observed for soluble fibrin. Postprandial mean values of triglycerides, FVIIa, FVII:Ag, and FVIIa/FVII:Ag were significantly higher for the high-fat diet than for the low-fat diet. Our findings confirm that high-fat meals cause immediate activation of FVII. The clinical implication is debatable because FVII activation was not accompanied by an increase in plasma F1+2 concentrations in patients with severe atherosclerosis. However, a local thrombin generation on the plaque surface cannot be excluded.
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PMID:Dietary factor VII activation does not increase plasma concentrations of prothrombin fragment 1+2 in patients with stable angina pectoris and coronary atherosclerosis. 1107 58

Several studies have previously reported high levels of total tissue factor pathway inhibitor (TFPI) antigen in patients with hypercholesterolemia. The relationship between serum lipid concentrations and total and free-form TFPI antigen in 32 patients with primary type II hypercholesterolemia and 38 age- and gender-matched normolipemic control subjects was studied (Study Group I). Plasma concentrations of total TFPI (tTFPI) antigen, free-form TFPI (fTFPI) antigen, tissue factor antigen, factor VII activity (FVIIc), and prothrombin fragment 1+2 (F1+2) were measured. The median levels of tTFPI, fTFPI, FVIIc, and F1+2 were higher in hyperlipidemic patients compared with those in healthy subjects. The effect of lowering total cholesterol on hypercoagulability in 25 patients with type II hyperlipoproteinemia (Study Group II) were also studied. The median levels of tTFPI, FVIIc, and F1+2 decreased significantly after 6 months of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor therapy in the hypercholesterolemic patients. On the other hand, fTFPI did not change after therapy. Plasma tTFPI was strongly correlated with total cholesterol and low density lipoprotein (LDL)-cholesterol in hyperlipidemic patients. In contrast to the strong correlation between tTFPI and total cholesterol, the correlation between plasma fTFPI and total cholesterol was relatively poor. These results suggest that the activation of the anticoagulant system as well as the activation of the coagulation system may occur in association with hypercholesterolemia. Furthermore, the results of this study may suggest that lowering of total cholesterol in hyperlipidemic patients reduces the thrombin generation in plasma and that down-regulation of LDL does not affect the anticoagulant potency of TFPI in plasma.
Atherosclerosis 2001 Jan
PMID:Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients. 1113 1

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


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