Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.
 ...
PMID:Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. 778 64

Growing evidence suggests that moderately elevated levels of homocysteine are associated not only with arterial thrombosis and atherosclerosis but also with venous thrombosis as well. We have reviewed recent studies that indicate that homocysteine inhibits several different anticoagulant mechanisms that are mediated by the vascular endothelium. The protein C enzyme system appears to be one of the most important anticoagulant pathways in the blood. Homocysteine inhibits the expression and activity of endothelial cell surface thrombomodulin, the thrombin cofactor responsible for protein C activation. Homocysteine inhibits the antithrombin III binding activity of endothelial heparan sulfate proteoglycan, thereby suppressing the anticoagulant effect of antithrombin III. Homocysteine also inhibits the ecto-ADPase activity of human umbilical vein endothelial cells (HUVECS). Because ADP is a potent platelet aggregatory agent, this action of homocysteine is prothrombotic. Homocysteine also interferes with the fibrinolytic properties of the endothelial surface because it inhibits the binding of tissue plasminogen activator. Homocysteine stimulates HUVEC tissue factor activity. We have found that lipoprotein(a) [Lp(a)] also stimulates HUVEC tissue factor activity. The combination of Lp(a) plus homocysteine induced more tissue factor activity than either agent alone. These disruptions in several different vessel wall-related anticoagulant functions provide plausable mechanisms for the occurrence of thrombosis in hyperhomocysteinemia.
 ...
PMID:Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. 864 72

Hyperhomocysteinemia is associated with severe, premature atherosclerosis and thromboembolism. The mechanisms involved in the atherogenic and thrombotic complications of hyperhomocysteinemia are not understood. It has been suggested that hyperhomocysteinemia predisposes to atherosclerosis by injuring the vascular endothelium. Whether hyperhomocysteinemia is independently associated with changed endothelial function, either in the absence or the presence of clinically manifest atherosclerotic disease, is, however, not known. Therefore we investigated, both in patients with peripheral arterial occlusive disease and in healthy individuals, whether plasma protein markers of endothelial function differed between subjects with, and subjects without hyperhomocysteinemia. We studied 80 individuals under the age of 56 years: healthy individuals with (n = 20) and without (n = 20) hyperhomocysteinemia and patients with peripheral arterial occlusive disease with (n = 20) and without (n = 20) hyperhomocysteinemia. The following endothelium-derived proteins were measured as markers of endothelial cell function: von Willebrand factor (vWf) and von Willebrand factor propeptide (vWf: AgII), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), cellular fibronectin (cFN) and thrombomodulin (TM). In addition we assessed C-reactive protein (CRP). vWf, vWf: AgII, tPA and CRP were significantly higher in the patients with peripheral arterial occlusive disease than in the healthy individuals. No differences in marker protein plasma levels were found between individuals with, and those without hyperhomocysteinemia, apart from vWf, which was significantly raised in hyperhomocysteinemic as compared to normohomocysteinemic patients. We did not find any evidence for an independent association between hyperhomocysteinemia and protein markers of endothelial cell function in healthy subjects.
 ...
PMID:Endothelial marker proteins in hyperhomocysteinemia. 940 14

The prevention of coronary artery disease is based on the control of several factors associated with a disease or clinical condition and suspected to play a pathogenetic role, defined as 'risk factors'. Smoking is a powerful risk factor for coronary artery disease, with risk of events increasing in relation to the number of cigarettes smoked daily. Smoking cessation is associated within 3-4 years, with a significant reduction in cardiovascular risk. Hyperlipidaemia is a powerful predictor of coronary disease with a strong, independent, continuous and graded positive association between cholesterol levels and risk of coronary events. Several large studies have shown the benefit of cholesterol reduction, and there is clear evidence of the efficacy of statins in the reduction of events in primary and secondary prevention. Hypertension is a significant, strong and independent risk factor for coronary artery disease morbidity and mortality and the reduction of events and mortality by antihypertensive treatment is well documented. Obesity is associated with an increase in all-cause mortality and cardiovascular mortality, with a particularly high risk for subjects with central obesity. Central obesity is also part of the so-called 'metabolic X syndrome' including insulin resistance, which appears to be associated with a particularly high risk of coronary artery disease. Type 1 and type 2 diabetes mellitus are associated with an increased risk of cardiovascular disease, especially in women. Several studies have shown that good metabolic control and multifactorial risk factor reduction significantly lower the coronary risk in these patients. Recent evidence is accumulating that some clotting factors (fibrinogen, factor VII, von Willebrand factor) and fibrinolytic factors (t-PA and PAI-1) are associated with an increased risk of coronary artery disease. The European Concerted Action on Thrombosis (ECAT) showed that the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent coronary syndromes in patients with angina pectoris, and that low fibrinogen is associated with a low risk of events despite high cholesterol levels. Post-menopausal status is associated with increased risk of coronary artery disease, particularly when menopause is premature (before the age of 45) or abrupt (surgical). There is strong, thought not yet completely definite evidence that post-menopausal hormone replacement therapy may significantly reduce the risk of events and improve survival. Hyperhomocysteinaemia is an emerging risk factor independently associated with an increased risk of coronary artery disease, cerebral vascular disease, and peripheral vascular disease. The administration of vitamin B6, B12 or folate seems to be useful and is currently under further evaluation. Recently, attention has been focused on the correlation between coronary artery disease and genetic factors, such as ACE gene polymorphism or the gene polymorphism for the IIIa-moiety of the platelet fibrinogen receptor IIb-IIIa. In primary prevention, control of the major risk factors mainly in patients with clustered factors will substantially reduce the risk of ischaemic events. Secondary prevention of CHD is based on: aggressive behavioural advice, blood pressure reduction in hypertensives, good metabolic control of diabetes, and cholesterol reduction. Aspirin, beta-blockers, ACE inhibitors, and oral anticoagulants, may be useful in selected patients.
 ...
PMID:Classical risk factors and emerging elements in the risk profile for coronary artery disease. 951 44

In order to elucidate the relationship between homocysteine and the fibrinolytic system, we examined the effect of homocysteine on plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) gene expression and protein secretion in cultured human vascular endothelial and smooth muscle cells in vitro. PAI-1 mRNA and secreted protein levels were both enhanced by homocysteine in a dose dependent manner, with significant stimulation of PAI-1 secretion observed at concentrations greater than 0.5 mM homocysteine. In contrast, secretion and mRNA expression of tPA were not significantly altered by homocysteine stimulation. Secretion of TGFbeta (transforming growth factor beta) and TNFalpha (tumor necrosis factor alpha), possible regulators of PAI-1 expression and secretion, were not stimulated by treatment with 1.0 mM homocysteine. These results suggests that hyperhomocysteinemia-induced atherosclerosis and/or thrombosis may be caused by homocysteine-induced stimulation of PAI-1 gene expression and secretion in the vasculatures by a mechanism independent from paracrine-autocrine activity of TGFbeta and TNFalpha.
 ...
PMID:Enhancement by homocysteine of plasminogen activator inhibitor-1 gene expression and secretion from vascular endothelial and smooth muscle cells. 1087 24

Mild hyperhomocysteinemia is recognized as a risk factor for venous thromboembolism (VTE), though its role in the thrombogenic processes is not understood. Its possible association with impaired fibrinolysis was investigated in 157 patients (61 women, 96 men) below the age of 60 years (43+/-11, mean+/-SD) with a history of objectively confirmed VTE. Patients had significantly higher fasting total plasma homocysteine (tHcy) levels than 138 apparently healthy subjects (8.0, 6.6-9.9 micromol/L vs. 7.2, 5.9-8.6 micromol/L, P=0. 001; median, range between first and third quartile). In 17 of 157 patients (12%) hyperhomocysteinemia (tHcy>11.4 micromol/L for women and tHcy>12.6 micromol/L for men) was established. The adjusted odds ratio as an estimate of relative risk for VTE was 2.3 (0.8-7.0; 95% confidence interval). When patients with hyperhomocysteinemia were compared to patients without hyperhomocysteinemia, no significant differences in t-PA (antigen 9.2+/-5.5 microg/L and 9.7+/-4.7 microg/L, respectively; activity 1.3+/-0.5 IU/mL and 1.3+/-0.7 IU/mL, respectively) and PAI-1 (antigen 19.3+/-17.5 microg/L and 22.6+/-20. 4 microg/L, respectively; activity 15.0+/-12.6 and 15.8+/-13.3 IU/mL, respectively) were observed. In conclusion, this study showed an association between mild hyperhomocysteinemia and VTE, but provided no evidence for an independent association between hyperhomocysteinemia and alterations in fibrinolytic proteins.
 ...
PMID:Mild hyperhomocysteinemia and fibrinolytic factors in patients with history of venous thromboembolism. 1111 70

Diabetics die mainly from thrombotic complications and there is clear evidence that diabetes is a hypercoagulable state. Epidemiological and prospective intervention data link hyperglycemia to vascular complications and glycation of proteins is one favored molecular basis to explain this fact. Cell surface receptors may support fibrinolytic surveillance in both intravascular and extravascular locations by stimulating plasmin generation and by protecting plasmin from its inhibitors. The existing experimental evidence suggests that annexin II in its tetrameric form is the main physiological receptor for plasminogen on the extracellular surface of endothelial cells. We have recently shown that annexin II is an extremely vulnerable target for glycation, quickly responding to restoration of normoglycemia. We hypothesize that glycation of endothelial membrane annexin II impairs the appropriate formation of the plasminogen/tissue plasminogen activator/annexin II complex, disrupting a key regulatory mechanism in fibrinolytic vigilance. This would in turn produce decreased fibrinolytic activity and indirectly promote a thrombophilic state in diabetic patients. We base our hypothesis on our observation and on evidence for the mechanism of action of two major independent risk factors for CV events: lipoprotein (a) and hyperhomocysteinemia. Binding of plasminogen to annexin II is inhibited by Lp (a) and binding of tissue plasminogen activator to annexin II is blocked by homocysteine. If our hypothesis is correct, one of the components of the increased thrombogenicity seen in diabetic patients might then be an acquired annexinopathy.
 ...
PMID:Is diabetic hypercoagulability an acquired annexinopathy? Glycation of annexin II as a putative mechanism for impaired fibrinolysis in diabetic patients. 1220 47

Hyperhomocysteinaemia is a prothrombotic condition that may cause oxidative endothelial injury and impair endogenous fibrinolysis. Vitamin supplementation enhances endothelial function in hyperhomocysteinaemic patients, but responses in patients with co-existing coronary artery disease have been variable. It is also unknown whether hyperhomocysteinaemia is associated with reduced fibrinolytic responses in patients with coronary artery disease. The study aims were to test the hypothesis that patients with recent myocardial infarction and hyperhomocysteinaemia have impaired endothelium-dependent vasomotion and fibrinolysis that is rectified by vitamin supplementation. From a cohort of 120 patients admitted with acute myocardial infarction, 18 patients were recruited from the upper (n=9) and lower (n=9) plasma homocysteine quartiles into a randomized double-blind placebo-controlled crossover trial. Following a 4-week course of placebo or folate/cyanocobalamin/pyridoxine supplements, FBF (forearm blood flow) was measured using venous occlusion plethysmography during intra-arterial substance P (4-16 pmol/min), acetylcholine (5-20 microg/min) and sodium nitroprusside (2-8 microg/min) infusions. All vasodilators caused dose-dependent increases in infused FBF (P<0.05). Patients in the upper homocysteine quartile (16.8+/-2.9 compared with 7.9+/-0.7 micromol/l; P=0.003) had reduced vasodilatation to acetylcholine (P=0.01) and substance P (P<0.05), but not sodium nitroprusside. There were no differences in substance P-induced tissue plasminogen activator release. Vitamin supplementation increased serum folate and vitamin B12 concentrations (P<0.05), but did not significantly lower homocysteine, or affect FBF or fibrinolytic responses. In patients with recent myocardial infarction, hyperhomocysteinaemia is associated with impaired endothelium-dependent vasodilatation, but no alteration in the acute fibrinolytic capacity. This endothelial vasomotor dysfunction is unaltered by vitamin supplementation.
 ...
PMID:Endothelial dysfunction in patients with recent myocardial infarction and hyperhomocysteinaemia: effects of vitamin supplementation. 1536

Hyperhomocysteinemia is a risk factor for arterial vascular disease and venous thrombosis. The pathophysiology of this relation is unclear, but several studies suggest that hyperhomocysteinemia impairs endothelial function. We examined the effect of homocysteine lowering by B-vitamin supplementation on tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI) and von Willebrand factor (vWf)--markers of endothelial dysfunction--in hyperhomocysteinemic and normohomocysteinemic volunteers. A total of 123 healthy volunteers were randomized to placebo or B-vitamins (5 mg folic acid, 0.4 mg hydroxycobalamin and 50 mg pyridoxine) daily for 8 weeks. Before and after the intervention period, blood samples were taken for measurements of homocysteine, tPA, PAI and vWf. There was no evident association between homocysteine concentration and concentrations of markers of endothelial dysfunction at baseline. The mean reduction of homocysteine concentration was 31% (95%CI 22.7 to 39.1) in the B-vitamin group compared to 3% reduction in the placebo group. Concentrations of tPA, PAI and vWf did not change after supplementation of B-vitamins. In conclusion, the results of our study show that homocysteine reduction by B-vitamin supplementation has no effect on markers of endothelial dysfunction in healthy volunteers.
 ...
PMID:The effect of homocysteine reduction by B-vitamin supplementation on markers of endothelial dysfunction. 1554 37

Hyperhomocysteinemia (HH) is an independent risk factor for thrombosis although the precise pathogenesis is still unresolved. Previous studies have demonstrated that HH changes whole blood coagulation by increasing the velocity, increasing the firmness of the formed clot, and by prolonging the initiation phase of the coagulation. With the aim of elucidating the genetic pathogenesis which might be responsible for the changes in whole blood coagulation, we applied oligo-array technology to RNA from buffycoat-cells comparing animals suffering from hyperhomocysteinemia (42 micromol/l) with controls (6 micromol/l). Data mining identified a number of relevant genes, and the expression pattern was validated by real time reverse transcriptase-polymerase chain reaction. An upregulation of integrin beta-3, Rap 1b, glycoprotein V, platelet-endothelial cell adhesion molecule-1 (PECAM-1) and von Willebrand factor (vWF) led us to deduce increased platelet activation/aggregation. Coagulation factor XIIIa was upregulated and may contribute in increasing the firmness of the formed clot. Impaired fibrinolysis was anticipated, since an upregulation of plasminogen activator inhibitor-1 (PAI-1) and a downregulation of tissue-type plasminogen activator (t-PA) were detected. Reduced spontaneous contact activation was anticipated due to a downregulation of the kallikrein gene. Upregulation of selectins may contribute to increased tethering and rolling of leukocytes. In conclusion, folate deficiency induced hyperhomocysteinemia changes in the gene expression of buffy coat cells which was characterized by increased platelet activation, impaired fibrinolysis and a reduced contact activation of the coagulation. These changes may contribute to explain the increased risk of thrombosis seen in hyperhomocysteinemia individuals. This pattern of the hyperhomocysteinemia-affected genes may represent a reference for further studies at the protein level to define the folate depletion effects in blood cells.
 ...
PMID:Folate deficiency induced hyperhomocysteinemia changes the expression of thrombosis-related genes. 1665 72


1 2 Next >>