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)

Endogenous tissue-type plasminogen activator (tPA) has been hypothesised to be a marker of baseline fibrinolytic capacity. We therefore tested whether tPA antigen is associated with the occurrence of future myocardial infarction (MI) among apparently healthy individuals. tPA antigen concentrations were measured at baseline in plasma samples from 231 apparently healthy men from the Physicians' Health Study cohort who later developed MI, and in an equal number of controls matched for age and smoking habit who remained free of reported cardiovascular disease during a follow-up of 60.2 months. In crude matched-pair analyses, baseline concentrations of tPA antigen were higher in cases than controls (p = 0.03) and strongly associated with risk of future MI. Specifically, the relative risks of developing a first MI from lowest (referent) to highest quintiles of tPA antigen were 1.00, 1.27, 1.75, 1.88, and 2.81 (p for trend 0.0008, 95% CI for the relative risk in the fifth as compared with first quintile 1.47 to 5.37, p = 0.002). Analyses which adjusted for risk factors that affect progression of atherosclerosis, particularly HDL-cholesterol, abolished the statistical significance of this association, a finding which suggests that elevations of tPA antigen are a result rather than a cause of atherosclerotic coronary disease. These prospective data suggest that endogenous tPA concentrations increase as a consequence of important preclinical atherosclerosis and therefore may be a marker for risk of future MI.
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PMID:Endogenous tissue-type plasminogen activator and risk of myocardial infarction. 810 Mar 14

Thrombin, the final product of blood coagulation cascade, shows several effect on the vessel-wall cells. However the effects may be regulated by several thrombin receptors on the endothelium. They include thrombomodulin (TM), protease-Nexin, heparin-like molecule-antithrombin III complex. These binding sites do not transduce the signal of thrombin. Especially TM converts thrombin from a procoagulant protease to an anticoagulant. Recently new thrombin receptor was identified on the endothelium and platelets. Through this receptor, thrombin induces activations both on platelet end-endothelium. In brief platelets aggregate and release several factors including serotonin, PDGF, platelet factor4, beta-thromboglobulin on the stimulation by thrombin. The endothelium release t-PA inhibitor; PAI-1, prostacyclin and endothelin. Thus the activations of these cells by thrombin is a key events in hemostasis, wound healing, inflammation, atherosclerosis and restenosis of coronary artery after PTCA.
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PMID:[Regulation of the endothelial function by thrombomodulin and/or thrombin receptor]. 815 41

The relationship between lipoprotein (a) (Lp(a)) and atherosclerosis has been appreciated for a number of years. Only in recent years, however, has the structural relationship of Lp(a) to plasminogen resulted in studies of the effect of this lipoprotein on fibrinolysis. Lp(a) inhibits activation of plasminogen by tissue-type (t-PA) and urinary-type (u-PA) plasminogen activators. These inhibitory reactions are surface-dependent. When Lp(a) binds to fibrin, fibrinogen, heparin or cells it blocks activation of plasminogen by t-PA. u-PA-mediated activation of plasminogen is blocked on surfaces including heparin and chondroitin sulfate. Lp(a) also favors inhibition of plasmin by alpha 2-antiplasmin (alpha 2-AP). The ability of Lp(a) to compete with plasmin for fibrin binding displaces plasmin into solution where alpha 2-AP rapidly inhibits this proteinase. These effects are all antifibrinolytic. Lp(a) also exhibits one profibrinolytic effect, since it blocks inhibition of t-PA by plasminogen activator type 1 in the presence of fibrinogen or heparin. Thus, Lp(a) modulates most of the reactions involved in plasmin generation and inhibition. Its overall effect will depend primarily on the concentrations of Lp(a), PAI-1 and t-PA in vivo.
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PMID:Lipoprotein (a) regulates plasmin generation and inhibition. 818 36

Elevated levels of endogenous tissue-type plasminogen activator (t-PA) appear to be a marker for preclinical atherosclerosis. At present, however, data describing potential relations between plasma t-PA level and established lipid risk factors for coronary atherosclerosis are sparse. To explore these potential relations, we measured plasma levels of t-PA antigen (t-PA:ag) in 633 apparently healthy men in the Physicians' Health Study as well as total cholesterol, high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, HDL3 cholesterol, and apolipoproteins A-I, A-II, and B-100. Overall, plasma t-PA:ag levels were inversely correlated with HDL cholesterol (r = -.1616, P < .0005), HDL2 cholesterol (r = -.1632, P < .0005), and HDL3 cholesterol (r = -.0927, P = .019). In stratified analyses, the inverse association between t-PA:ag and HDL cholesterol was present among frequent (P trend = .002) and infrequent (P trend = .004) consumers of alcohol as well as among the subgroups of frequent exercisers (P trend < .001), men in the lower half of body mass index (P trend = .001), and nonsmokers (P trend < .001). In contrast, there was no association between t-PA:ag and total cholesterol (r = .0219, P = .58), whereas relations of t-PA:ag with apolipoproteins A-I, A-II, and B-100 were minimal and of borderline significance. These data indicate that plasma levels of endogenous t-PA:ag are inversely related to HDL cholesterol as well as HDL2 and HDL3 cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A cross-sectional study of endogenous tissue plasminogen activator, total cholesterol, HDL cholesterol, and apolipoproteins A-I, A-II, and B-100. 821 99

The fibrinolytic capacity of blood depends mainly on the amount of tissue-type plasminogen activator (t-PA) activity and plasminogen activator inhibitor type-1 (PAI-1) activity. Previous studies linked high PAI activity or low t-PA activity with the development of atherosclerosis and thromboembolic diseases. Yet, there are conflicting reports in the literature as to whether there is higher PAI activity in patients with myocardial infarction (MI) than in patients with coronary artery disease (CAD) without previous MI. In this retrospective study, t-PA activity, t-PA antigen, and PAI activity before and after a venous occlusion test (VOT) of 10 min were assessed in 109 patients with angiographically documented CAD, in two subgroups of CAD patients with (n = 66) or without (n = 43) previous MI, and in subgroups of CAD patients according to their triglyceride levels and other risk factors. The mean values of t-PA activity in the whole patient group showed a 100-fold increase and a 3.1-fold increase in t-PA antigen after VOT (0.03 +/- 0.03 to 3.0 +/- 6.8 U/ml and 16.5 +/- 6.9 to 51.0 +/- 25.4 ng/ml, p < 0.05). PAI activity was 24.4 +/- 11.0 before and 19.6 +/- 13.2 U/ml after VOT. Within the CAD group, no difference was found between patients without MI and survivors of previous MI in PAI activity before VOT (24.6 +/- 10.7 vs. 24.3 +/- 11.3 U/ml) and after VOT (19.0 +/- 12.1 vs 20.0 +/- 14.0 U/ml), or t-PA activity before (0.03 +/- 0.01 vs. 0.04 +/- 0.04 U/ml) and after VOT (2.8 +/- 7.0 vs. 3.2 +/- 6.7 U/ml). In 39.4% of CAD patients elevated plasma PAI activity before VOT (> 25 U/ml) was found. This subgroup of patients represented the highest PAI activity after VOT (p < 0.05), the lowest t-PA activity after VOT (p < 0.001), and the highest triglyceride levels (p < 0.05). In 11% of the patients, a small increase in t-PA activity (less than 0.5 U/ml) after VOT was seen. This group showed the lowest t-PA antigen after VOT (p < 0.001) and the highest fibrinogen level (p < 0.05). Both subgroups showed the same distribution among patients with and without MI. CAD patients with triglyceride levels over 200 mg/dl had the highest PAI activity values before VOT (28.3 +/- 11.8 U/ml; p < 0.01) and after VOT (24.9 +/- 13.2 U/ml; p < 0.01), resulting in low t-PA activity after VOT (p < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:High PAI activity with correlation to triglyceride and HDL cholesterol values in patients with coronary artery disease with no difference in survivors of myocardial infarction. 824 47

Accelerated atherosclerosis is the leading cause of death in patients with non-insulin-dependent diabetes mellitus (NIDDM). Impaired endogenous fibrinolytic activity may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi and clot-associated mitogens. This study was conducted to further characterize endogenous fibrinolysis in lean and obese nondiabetic subjects and in NIDDM patients and to identify mechanisms responsible for the alterations identified. Obese and diabetic subjects had threefold elevations of plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1) compared with values in lean control subjects. Despite the lack of significant differences in plasma concentrations of tissue-type plasminogen activator in the obese and diabetic subjects, both basal and stimulated endogenous fibrinolytic activities were decreased. The decreases were associated with increased activity of PAI-1 in plasma, in turn correlated with increased concentrations of immunoreactive insulin and C-peptide. These results are consistent with our previous observations demonstrating direct stimulatory effects of insulin and its precursors on cellular expression of PAI-1 in vitro and observations by others demonstrating decreased basal fibrinolytic activity in NIDDM patients. Impaired endogenous fibrinolytic activity could lead to prolonged or recurrent exposure of luminal surfaces of vessel walls to microthrombi and clot-associated mitogens that may accelerate atherosclerosis in hyperinsulinemic subjects.
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PMID:Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. 826 7

Angiographic demonstration of luminal narrowing during pulse-spray pharmacomechanical thrombolysis (PSPMT) may reflect residual lysable clot, organized thrombus, platelet-rich clot, atherosclerosis, neointimal hyperplasia, or functional narrowing. The authors evaluated the efficacy and safety of lytic stagnation (initial rapid lysis followed by insubstantial further lysis with additional treatment) as an end point for PSPMT. Lytic stagnation was evaluated with serial angiography in 16 arterial and five bypass graft occlusions. Substantial lysis occurred after administration of mean doses of 512,000 units +/- 182,000 of urokinase or 5.3 mg +/- 2.0 of tissue-type plasminogen activator. Additional treatment with either of those agents produced minimal or no further change in the appearance of residual disease. Recanalization was successful in all patients after angioplasty. Distal emboli were noted in four cases, in three of which angioplasty of large intraluminal filling defects had been performed. The authors conclude that lytic stagnation is a reliable and safe end point for PSPMT in the absence of large intraluminal filling defects.
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PMID:Occluded peripheral arteries and bypass grafts: lytic stagnation as an end point for pulse-spray pharmacomechanical thrombolysis. 832 83

The capacity of macrophages to influence directly and indirectly fibrinolytic processes in atherosclerosis was studied using macrophages isolated from atherosclerotic plaques of patients undergoing surgical repair of distal aortic and femoral arteries. These cells were characterized by their morphology, adherence, esterase positivity, and expression of CD14 antigen. Production of plasminogen activator inhibitor type-1 (PAI-1) by plaque macrophages (6.7 +/- 2.7 ng/10(5) cells/24 hours [mean +/- SEM]) was significantly greater than PAI-1 production by blood monocytes isolated simultaneously from the same patients (1.8 +/- 1.5 ng/10(5) cells/24 hours). Production of tissue type plasminogen activator and urokinase type was not augmented compared to blood monocytes. Conditioned medium from cultured plaque macrophages significantly increased production of PAI-1 by endothelial cells (85 +/- 11% above basal) and vascular smooth muscle cells (25 +/- 10%) in vitro. This response was significantly greater than the response to monocyte-conditioned medium (endothelial cells 38 +/- 11%, vascular smooth muscle cells 2.5 +/- 2.0%). Stimulation of endothelial cell PAI-1 production by macrophage-conditioned medium was partially inhibitable by a monoclonal antibody to transforming growth factor-beta. Tissue type plasminogen activator production by endothelial cells and vascular smooth muscle cells was not affected by plaque macrophage- or monocyte-conditioned medium. Urokinase type plasminogen activator production by endothelial cells and vascular smooth muscle cells was undetectable in control medium and was augmented to similar levels in response to plaque macrophage- and monocyte-conditioned media. These results demonstrate upregulation of PAI-1 production by macrophages in atheromatous plaques and the capacity of soluble products from plaque macrophages to upregulate PAI-1 production by endothelial cells and vascular smooth muscle cells in vitro. These data suggest that macrophages in atherosclerotic plaques may inhibit thrombolysis both directly and indirectly by effects of their soluble products on endothelial cells and vascular smooth muscle cells.
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PMID:Atheromatous plaque macrophages produce plasminogen activator inhibitor type-1 and stimulate its production by endothelial cells and vascular smooth muscle cells. 836 83

Six healthy male volunteers were served 4 strictly controlled isoenergetic diets differing in fat (20% or 50% of energy) and fiber contents (2 or 4 g/MJ) for periods of 2 days. The diets were served in random order with at least 5 days separating each diet period. Blood samples for determination of factor VII clotting activity using human (FVIIc) and bovine thromboplastin (FVIIbt), and for assessment of factor VII antigen (FVIIag), tissue-plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1) antigen, PAI activity, t-PA and euglobulin fibrinolytic activity, and triglyceride and insulin levels were collected regularly on the second day of each diet period. The high-fat diets resulted in significantly increased postprandial FVIIbt levels (peak values: 131% vs. 95%, P < 0.01), and higher postprandial FVIIbt/FVIIag ratios (peak values: 1.42 vs. 1.16, P < 0.01) compared with the low-fat diets. Fibrinolytic variables were not affected by the dietary changes and consistently showed characteristic U-shaped (t-PA and PAI-1 antigen, PAI activity), or inverted U-shaped (t-PA and euglobulin fibrinolytic activity) circadian patterns with troughs and peaks, respectively, at 17:30-21:30 h. The dietary fiber content had no significant influence on any of the measured variables. Our findings indicate that high-fat diets may increase blood thrombogenicity by virtue of augmented postprandial activation of factor VII.
Atherosclerosis 1993 Jul
PMID:Dietary effects on circadian fluctuation in human blood coagulation factor VII and fibrinolysis. 839 16

Several haemostatic factors have been shown to have a predictive role in cardiovascular disease, although their relationship with prevalent peripheral arterial disease is not well reported. Using a random sample of 1592 men and women aged 55-74 years from Edinburgh, Scotland, we examined the relationship of von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and fibrin D-dimer antigens and factor VII activity to peripheral arterial disease. t-PA antigen and fibrin D-dimer showed significant linear trends of increased levels with increasing severity of disease in both sexes (p < or = 0.01) and vWF showed a similar pattern in men only (p < or = 0.01). On multivariate analysis, fibrin D-dimer was independently related to the risk of intermittent claudication (p < or = 0.01) and, among men, to the extent of arterial narrowing in the lower limb, as measured by the ankle brachial pressure index, (ABPI) (p < or = 0.001). These results are further evidence of a role for intravascular fibrin deposition in the development of peripheral atherosclerosis.
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PMID:Fibrin D-dimer, haemostatic factors and peripheral arterial disease. 857 5


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