Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in coagulation and fibrinolysis in the plasma (in vivo) and hepatocytes (ex vivo) were studied using hyperglycemic rats. Hyperglycemia was induced by intravenous injection of 50 mg/kg streptozotocin (STZ). Eight weeks after the injection, we observed increases in thrombin-antithrombin III complex and tissue type plasminogen activator activity, decreases in plasma levels of antithrombin III, plasminogen and alpha2-plasmin inhibitor, and significant shortening of activated partial thromboplastin time. In freshly isolated or cultured hepatocytes from STZ-induced hyperglycemic rats, concentrations of proteins related to coagulation were increased. An increase in alanine-aminotransferase leakage and decreases in the levels of amylase, triglycerides and phospholipids were observed in the culture medium of hepatocytes from STZ treated rats. In vivo study revealed that STZ-induced subchronic diabetes induced imbalance between coagulation and fibrinolysis, and ex vivo study in hepatocytes from STZ-treated rats showed membrane degeneration and reduction in amylase synthesis, while protein synthesis related to coagulation was not inhibited. These results suggest that, despite vulnerability of liver cells from STZ treated rats, coagulation activity in the liver is retained and rather enhanced in STZ-induced hyperglycemic rats, which may contribute to the promotion of atherosclerosis.
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PMID:Blood coagulability and fibrinolysis in streptozotocin-induced diabetic rats. 958 51

Strong evidence from large observational epidemiological studies links haemostatic variables to the future risk of myocardial infarction and stroke. Recent data provide further evidence for an early involvement of haemostatic parameters in atherosclerosis. So far, a variety of markers of a procoagulatory tendency e.g. elevated fibrinogen, coagulation factor VII, factor VIII and von Willebrand factor, platelet hyperaggregation, increased plasma levels of D-dimer, and decreased fibrinolytic capacity, e.g. characterized by increased levels of PAI-1 activity and decreased t-PA concentrations have been identified prospectively. Thus, a complex disturbed haemostatic system plays an important role in the development of atherothrombotic events in several vascular beds. This review discusses the epidemiologic evidence of the association between the haemostatic system and cardiovascular disease.
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PMID:Haemostatic risk factors for cardiovascular diseases. 959 24

The multiligand receptor, low density lipoprotein receptor-related protein (LRP), is implicated in processes such as atherosclerosis and fibrinolysis through its mediation of the catabolism of lipoproteins, proteases, and protease inhibitor complexes. The hepatoma cell line Hep G2 expresses LRP and has been used widely to investigate the catabolism of LRP ligands including tissue-type plasminogen activator (tPA). However, the mechanism and degree by which tPA interacts with Hep G2 has been reported with some inconsistencies which may reflect variation in their level of LRP expression. To address this possibility we characterized, antigenically and functionally, LRP expression in high and low passage Hep G2 cells both from the parental line (ATCC sourced) and a cloned subline, a16. The LRP contribution to 125I-tPA binding varied from 65% for high passage a16 cells, to 20% for low passage parent cells as quantified by inhibition in the presence of 39-kD receptor associated protein (RAP) which prevents binding of all known LRP ligands. The same trend in LRP expression among Hep G2 sublines was further evident in their ability to degrade 125I-tPA and survive Pseudomonas exotoxin A challenge. These results imply wide variability in basal LRP expression among Hep G2 lines dependent on cell lineage and long-term culture conditions.
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PMID:Low density lipoprotein receptor-related protein (LRP) expression varies among Hep G2 cell lines. 961 Sep 60

Epidemiological studies have demonstrated that levels of plasma fibrinogen, von Willebrand factor (vWf), plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) are associated with the incidence of vascular disease. Since oncostatin M dramatically induces fibrinogen biosynthesis by hepatocytes and could be implicated in vascular injury leading to atherosclerosis, we have analyzed the effect of oncostatin M on PAI-1, vWf and tPA secretion by endothelial cells. A 2-h incubation of human umbilical vein endothelial cells with oncostatin M increases thrombin-induced secretion of vWf to the same extent as tumour necrosis factor-alpha or interleukin-1 (137+/-26% of control for 5 ng/ml oncostatin M, P < 0.001, n=5). The effects on tPA and PAI-1 secretion were different depending on the type of endothelial cells tested. On human umbilical vein endothelial cells, oncostatin M induced an increase in PAI-1 and a decrease in tPA secretion, which could explain the thrombogenicity of oncostatin M on large vessels. On a human microvasculature endothelial cell line, oncostatin M did not modify PAI-1 but induced an increase in tPA secretion. This observation of the effects of oncostatin M on both macro- and microvasculature could explain the increased levels of vWf, PAI-1 and tPA in the plasma of atherosclerotic subjects identified in epidemiological studies, suggesting that oncostatin M could play a key role in the development of atherosclerotic lesions.
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PMID:In-vitro effect of oncostatin M on the release by endothelial cells of von Willebrand factor, tissue-type plasminogen activator and plasminogen activator inhibitor-1. 986 9

Increased concentrations of plasminogen activator inhibitor type 1 (PAI-1) and of D-dimer have jointly been found in subjects with cardiovascular disease. To understand this apparent paradox of increased inhibition of fibrinolysis (high PAI-1) combined with increased fibrinolytic activity (high D-dimer), we examined the relation between D-dimer, PAI-1 and the activator of fibrinolysis, tissue type plasminogen activator (t-PA) in subjects with varying severity of peripheral atherosclerosis. In 325 subjects selected from the Rotterdam Study, a cohort of 7983 men and women aged 55 years and over, the ankle to brachial systolic blood pressure ratio, t-PA antigen and activity, PAI-1 antigen and D-dimer were measured. T-PA antigen and t-PA activity were, independent from each other, increased with degree of atherosclerosis; t-PA antigen increased with 3.5 ng/ml (SE 1.7, p = 0.04) and t-PA activity with 0.46 IU/ml (0.20, p = 0.02) per unit decrease in ankle to brachial pressure ratio (i.e. increase in atherosclerosis). PAI-1 antigen was not related to atherosclerosis. More marked atherosclerosis was associated with increased D-dimer, mainly in subgroups with PAI-1 antigen below 50 ng/ml, t-PA antigen below 10 ng/ml, or t-PA activity above 1.5 IU/ml. In contrast to current beliefs, we found that only a fraction of the variation of t-PA antigen was due to the variation in circulating PAI-1 antigen. A slight positive association was observed between t-PA antigen and D-dimer. PAI-1 and t-PA activity were not associated with D-dimer concentration. In conclusion, in subjects with peripheral atherosclerosis PAI-1 antigen is not increased, but low PAI-1 levels (and possibly also low levels of t-PA antigen and high levels of t-PA activity) appear to be required to increase circulating D-dimer. This suggests that increased D-dimer levels in subjects with atherosclerosis do not reflect increased inhibition, but rather reflect increased fibrinolysis.
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PMID:Fibrinolytic activity in peripheral atherosclerosis in the elderly. 1006 6

Cyclosporin A (CsA) has been implicated as one of the factors contributing to the high cardiovascular morbidity and mortality after renal transplantation. This may be mediated by either a high prevalence of conventional risk factors for atherosclerosis, such as hypertension, hypercholesterolemia, and diabetes mellitus, or by impairment of the fibrinolytic activity evoked by CsA, possibly through interference with prostanoid metabolism. We therefore assessed the impact of conversion of CsA to azathioprine immunosuppressive treatment on parameters of fibrinolytic activity and plasma concentration of the prostanoids prostaglandin E2 and thromboxane B2 in 18 stable renal transplant recipients. During CsA, mean arterial pressure and serum creatinine were significantly higher than during azathioprine (116+/-15 mm Hg versus 106+/-13 mm Hg, P=0.0003; and 147+/-34 micromol/L versus 127+/-35 micromol/L, P=0.002; mean+/-SD). On conversion, the plasma tissue plasminogen activator activity increased from 1.2 (1.1 to 1.7; median, 95% CI) to 1.8 (1.6 to 2.0) IU/mL (P=0.011), without a significant change of the plasminogen activator antigen concentration. This was associated with a substantial decrease in plasminogen activator inhibitor-1 activity from 10.4 (8.5 to 16.7) to 6.4 (5.6 to 9.2) IU/mL (P=0.009). Furthermore, plasma levels of prostaglandin E2 and thromboxane B2 markedly decreased (from 9.7 [7.4 to 12.9] to 4.6 [4.3 to 8.1] pg/mL, P=0.0006; and from 106.1 [91.7 to 214.2] to 70.2 [50.3 to 85.6] pg/mL, P=0.002, respectively). During CsA, but not azathioprine, plasma tissue plasminogen activator antigen and plasminogen activator inhibitor-1 levels correlated significantly with prostaglandin E2 (r=0.53, P=0.02; and r=0.60, P=0.008, respectively), and thromboxane B2 (r=0.75, P=0.0001; and r=0.77, P=0.0001, respectively) levels. In conclusion, CsA induced substantial impairment of fibrinolytic activity, which recovered after conversion to azathioprine. The impaired fibrinolysis observed during CsA treatment may be caused by modulation of eicosanoid production or metabolism in vascular endothelial cells and possibly contributes to the high incidence of cardiovascular disease after kidney transplantation.
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PMID:Beneficial effects of conversion from cyclosporine to azathioprine on fibrinolysis in renal transplant recipients. 1036 89

During recent years it has become increasingly recognized that the plasmin activation system is involved in the development of atherosclerosis and restenosis. Responsible pathophysiologic mechanisms, however, remain elusive. This review focuses primarily on the clinicians, point of view, suggesting that increases in plasminogen activator inhibitor type-1 (PAI-1) plasma levels after balloon angioplasty or permanently elevated lipoprotein (a) (Lp(a)) plasma levels might be helpful in the prediction of restenosis after coronary angioplasty. In contrast, tissue-type plasminogen activator (tPA) plasma levels appear unrelated to restenosis, and data regarding a possible role of urokinase-type plasminogen activator (uPA) in circulation are not available at present. Furthermore, a new hypothesis on the pathophysiological role of local PAI-1 overexpression as a beneficial negative feedback mechanism to limit excess cellular proliferation in atherogenesis and restenosis is presented.
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PMID:Plasmin activation system in restenosis: role in pathogenesis and clinical prediction? 1037 89

Dysfunction in the vascular endothelium disturbs blood flow and predisposes individuals to atherosclerosis. Deteriorated fibrinolysis may further enhance the risk for atherothrombosis. We investigated 14 healthy volunteers and 24 patients with coronary heart disease. Endothelium-dependent (acetylcholine- and ischemia-induced) and endothelium-independent (nitroprusside-induced) vasodilatation in the forearm vasculature were studied using strain-gauge plethysmography, and the fibrinolytic system measured as the response of tissue plasminogen activator (t-PA) to provocation testing (20 min venous occlusion; VOT). When acetylcholine-induced vasodilatation was measured, endothelium-dependent vasodilatation differed between groups: those with coronary heart disease had a median value of 8.5 ml/min per 100 g tissue (25th to 75th percentile 4.8-10.3), compared with 11.6 ml/min per 100 g tissue (7.3-15.5) among healthy volunteers (P = 0.03). However, ischemia-induced vasodilatation showed no difference between the groups [26.8 (22.7-35.0) versus 29.1 (25.6-30.7) ml/min per 100 g tissue, respectively, NS]. Levels of t-PA after VOT also showed no difference between the groups [21.5 (16.5-31.9) versus 20.4 (11.8-31.5) ng/ml, respectively, NS]. Results of ischemia tests and levels of t-PA after VOT correlated only in patients with coronary heart disease (r = 0.5, P = 0.015), and not in healthy volunteers. We observed a positive correlation between endothelium-dependent vasodilatation function and endothelial release of t-PA. This indicates that the same mechanism that results in defective ischemia-induced endothelial relaxation in patients with coronary heart disease may also result in suppressed fibrinolytic capacity, thus making such patients more prone to atherothrombosis.
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PMID:Endothelial release of tissue-type plasminogen activator and ischemia-induced vasodilatation are linked in patients with coronary heart disease. 1039 Jan 17

An elevated plasma concentration of the soluble intercellular adhesion molecule-1 (sICAM-1) is associated with increased risk for future coronary events. However, data exploring the interrelations of sICAM-1 with known cardiovascular risk factors are sparse. We determined sICAM-1 levels in 948 middle-aged men with no prior history of cardiovascular disease. sICAM-1 levels increased with age (P<0.001) and were significantly associated with smoking (P<0.001), hypertension (P<0.05), and frequent alcohol consumption (P=0.006). Positive correlations were observed between sICAM-1 and triglycerides (r=0.15; P<0.001), fibrinogen (r=0.21; P<0.001), tissue-type plasminogen activator antigen (r=0.17; P<0.001), and total homocysteine (r=0.09; P=0.02); whereas a negative correlation was observed for high density lipoprotein cholesterol (r=-0.15; P<0. 001). Overall, plasma concentrations of sICAM-1 increased with increasing prevalence of usual cardiovascular risk factors; mean plasma concentrations were 231, 236, 245, 257, and 312 ng/mL for those subjects with 0, 1, 2, 3, and >4 risk factors, respectively (P<0.01 for trend). In multivariate analysis, age, smoking status, diabetes, systolic blood pressure, positive family history of coronary disease, and serum levels of total homocysteine and fibrinogen were all independently associated with sICAM-1 levels (all P</=0.05). sICAM-1 levels are associated with several established cardiovascular risk factors. Further studies will be needed to evaluate whether these associations reflect the role of sICAM-1 as a marker of preclinical atherosclerosis, and whether such interrelations might have a causal basis.
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PMID:Cross-sectional study of soluble intercellular adhesion molecule-1 and cardiovascular risk factors in apparently healthy men. 1039 75

The vascular endothelium is a biologically active monolayer of cells providing an interface between the blood flow and tissues. Vascular Endothelial Cells (VEC) have two functional states. The endothelium is normally anti-thrombotic and anti-adhesive to ensure blood fluidity. During aggressions, such as atherosclerosis, inflammation states, metabolic diseases (through chemical or mechanical stimuli), VEC can reverse its functions by expressing stored material or by slower involvement of previously are repressed genes. Endothelial cells have three types of anti-thrombotic properties: vaso regulating properties: VEC release vasomotor components, such as endothelin (vasoconstriction), prostacyclin and nitric oxide, (vasodilatation). Endothelial cells also have antithrombotic and hemostatic properties. They express proteoglycans on their surface, including some negative-charge, plasminogen, sulfate glycosaminoglycans (heparan-sulfate), and secrete plasminogen tissular activator (t-PA) and tissular factor inhibitor. One fundamental action of the endothelium in that area is the production and expression of thrombomodulin, a thrombin receptor. This function has a major anticoagulation effect, controlling continual thrombin generation at the sub-endothelium and blood cell interface. Moreover, endothelial cells show anti-adhesion properties. During cardio-vascular diseases, all of these properties may be reversed. Thus the VEC have a determinant role in hemodynamic control through these various metabolic activities, such as control of homeostasis, vascular tone, blood fluidity, coagulating properties, cellular adhesion. Otherwise, many studies have demonstrated that local blood flow conditions have a crucial role on the VEC properties (mechanoactivation and mechanotransduction concept). In conclusion, knowledge of all the properties of the endothelial cells and control of the phenomena which define their functions is a key element in understanding cardiovascular diseases.
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PMID:[Hemorheology and vascular endothelial cells]. 1039 42


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