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)

Epidemiological studies have associated moderate alcohol consumption with a reduced risk for coronary artery disease (CAD) and myocardial infarction (MI). This cardioprotection may be attributed to alcohol-induced changes in a variety of cellular functions, including increased fibrinolysis. Fibrinolysis is important in regulating normal hemostasis. Endothelial cells (ECs) synthesize fibrinolytic proteins, t-PA, u-PA, and PAs inhibitor, PAI-1. Systemic factors, i.e., alcohol, that affect one or more of these components, resulting in increased EC fibrinolysis, will reduce the risk for thrombosis, CAD, and MI and afford cardioprotection. These studies will identify/define the effects of low ethanol (< 0.1%, v/v) on the expression of PAs, PAI-1, and surface-localized fibrinolytic activity in cultured ECs. Low ethanol exerted a short-term time- and dose-dependent increase (approximately 5- to 8-fold) in activity at approximately 20 min and 0.05% ethanol, which was sustained for approximately 1 hr. On the other hand, a single brief exposure to low ethanol (< 0.1%, < 120 min), followed by 4-24 hr incubation in the absence of ethanol, showed a time- and dose-dependent increase (approximately 2- to 3-fold) in PAs antigen/mRNA and a concomitant approximately 2- to 3-fold sustained increase (approximately 24 hr) in fibrinolytic activity. Further nuclear transcription run-on assays and transient transfection experiments, using pPAs/luc and pPAI-1/luc promoter constructs, demonstrated that low ethanol transcriptionally upregulates t-PA and u-PA gene expression and downregulates PAI-1 gene expression. These combined studies have described a feasible molecular mechanism by which low ethanol can induce and sustain increased surface-localized EC fibrinolysis that may underlie and contribute, in part, to the cardioprotective benefit associated with moderate alcohol consumption.
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PMID:Endothelial cell fibrinolysis: transcriptional regulation of fibrinolytic protein gene expression (t-PA, u-PA, and PAI-1) by low alcohol. 1039 1

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.
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PMID:[Blood coagulation and fibrinolysis in arteriosclerosis]. 1041 53

Background: In epidemiologic studies, excessive body weight, independent of other risk factors, portends a poor prognosis among patients with coronary artery disease experiencing acute myocardial infarction (MI). At least one recent study has suggested that patients of excessive body weight when receiving thrombolytic therapy are often under-dosed, potentially reducing early coronary arterial patency and adversely affecting in-hospital clinical outcome. Concern has also been raised that body weight may influence treatment utilization, delays, and complication rates. Despite these concerns, the association between body weight and patient outcome following coronary thrombolysis has received limited attention. Methods/Results: Demographic, procedural, and outcome data from patients with MI were collected at 1073 United States hospitals participating in The National Registry of Myocardial Infarction from 1990 through 1994. Among 350,755 patients with MI enrolled, 87,688 (25.1%) were treated with tissue plasminogen activator (t-PA). Divided into body weight tertiles, 23.5% of patients were less than 70 kg (low weight), 36.8% were 70-85 kg (moderate weight), and 37.5% were greater than 85 kg (high weight). Patients of low weight were older (p < 0.001), received treatment later (p < 0.001), and were less likely to undergo cardiac catheterization, coronary angioplasty, or bypass surgery (p < 0.001) than moderate- or high-weight patients. Low-weight patients also experienced minor bleeding, major bleeding, recurrent MI, and death more often (p < 0.001). Adjusted for age, low body weight was independently associated with in-hospital mortality. Despite receiving a lower dose of t-PA per kg body weight, high-weight patients had a low incidence of cardiogenic shock, recurrent MI, death, and hemorrhagic complications.When high-weight women and men were compared, several interesting observations emerged. Mortality was increased twofold in women (6.8% vs. 3.0; p < 0.001), even adjusting for their older age. Despite being at increased risk, women were less likely than their male counterparts to undergo cardiac catheterization (p = 0.001) or bypass surgery (p = 0.008). Conclusions: The National Registry of Myocardial Infarction provides a unique resource for assessing health care trends in the United States. Our findings suggest that low body weight is associated with increased in-hospital morbidity and mortality. They also suggest that current dosing strategies for t-PA administration are probably adequate for high-weight patients. The excessive mortality and limited use of in-hospital interventions among high-weight women deserve further study to address gender-related differences in disease processes, as well as potential bias or discrimination.
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PMID:Association Between Body Weight and In-Hospital Clinical Outcome Following Thrombolytic Therapy: A Report from the National Registry of Myocardial Infarction. 1060 29

Although disturbances of the fibrinolytic system and serum lipid, and the presence of inflammation, may be risk factors for coronary artery disease (CAD), few reports have investigated these relationships in Japanese patients. Data on 106 patients (79 men and 27 women, mean age 62.3 years) with atherosclerotic lesions on the coronary angiogram were evaluated prospectively to identify whether the factors were useful in predicting the risk of coronary events during a follow-up of 50+/-4 months. Of the 106 patients who were followed, 11 patients had coronary events (4 acute myocardial infarction and 7 unstable angina pectoris). In univariate Cox analyses, a high level of tissue-plasminogen activator (t-PA), apolipoprotein CII, C-reactive protein (CRP), and a low level of high-density lipoprotein-cholesterol (HDL-C) was each associated with a significant increase in the risk of future cardiac events. The stepwise model of Cox proportional hazards analysis selected only a high level of t-PA and CRP as predictors of cardiac events. Controlling for any risk factor did not lower the relation between t-PA and the risk of cardiac events, whereas the relative risk of cardiac events in CRP was not significant when controlled for HDL-C. Thus, in prospective data obtained from a cohort of Japanese patients with coronary atherosclerotic lesions, the elevation of t-PA was an independent predictor of subsequent cardiac events. The prognostic role of CRP in cardiac events was related to a low level of HDL-C.
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PMID:Fibrinolytic factors, serum lipid and C-reactive protein predicting cardiac events in Japanese patients with coronary atherosclerotic lesions. 1061 44

Impaired fibrinolytic function, mainly due to increased plasma plasminogen activator inhibitor-1 (PAI-1) activity, is common in patients with manifest coronary artery disease (CAD) and a predictor of recurrent cardiovascular events. We investigated the relationships of plasma tissue-type plasminogen activator (tPA) and PAI-1 antigen levels, plasma PAI-1 activity and PAI 4/5-guanosine (4G/5G) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial (LOCAT). A higher tPA antigen concentration, whether baseline or on-trial, was associated with a more severe global angiographic response (p < 0.05), an association mainly accounted for by progression of diffuse lesions in graft-affected segments (change in per-patient means of average diameters of segments haemodynamically related to bypass grafts). Plasma PAI-1 activity and mass concentration and 4G/5G PAI-1 genotype were unrelated to angiographic outcome measurements. tPA and PAI-1 antigen increased significantly in the gemfibrozil group (+11.3% and + 16.4%, respectively, p < 0.001), whereas there was no treatment effect on PAI-1 activity (median change 0.0%). It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men. Furthermore, pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations.
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PMID:Fibrinolytic proteins and progression of coronary artery disease in relation to gemfibrozil therapy. 1074 43

Localized regulation of fibrinolytic protein gene expression is associated with the histologic extent of atherosclerosis. This regulation may be dependent on the presence of certain fibrinolytic protein gene polymorphisms. The relationship between the plasminogen activator inhibitor (PAI)-1 Hin dIII and the tissue plasminogen activator (t-PA) EcoR1 gene polymorphisms and the extent of coronary artery disease (CAD) were investigated in 49 Caucasian patients with symptomatic CAD. There was a strong association between PAI-1, but not t-PA, gene polymorphisms and the extent of CAD detected by coronary angiography. Patients homozygous for the presence or absence of the PAI-1 HindIII (1/1, 2/2 PAI-1) gene polymorphisms had a significantly greater extent of CAD (number of diseased vessels) than patients with the respective heterozygous forms (vs. 1/2 PAI-1, P&< = 0.05). Stepwise ordinal multiple regression analysis of classic CAD risk factors and fibrinolytic protein genotypes indicated that only the PAI-1 genotypes were predictive of the extent of angiographic CAD (P = 0.019). Analysis of variance between classic risk factors and fibrinolytic protein genotypes identified an association between t-PA genotypes and a history of prior infarction or stroke. Fibrinolytic gene polymorphisms for PAI-1 are associated with the extent of CAD in symptomatic patients and with certain risk factors for coronary atherosclerosis.
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PMID:Gene Polymorphisms for PAI-1 Are Associated with the Angiographic Extent of Coronary Artery Disease. 1076 9

Obesity is associated with an increased risk of atherosclerotic coronary artery disease. Cytokines and oxygen-centered free radicals implicated in insulin resistance stimulate adipocyte and endothelial production of plasminogen activator inhibitor type-1 (PAI-1), the primary physiologic inhibitor of fibrinolysis, in vitro. In obese hyperinsulinemic animal models simulating insulin resistance, plasma PAI-1 activity is increased. As the cardiovascular risk profile in specific populations may differ, endogenous fibrinolysis in lean and obese subjects was characterized and the mechanisms underlying differences were identified. Obese subjects (body mass index > 26) exhibited increased blood levels of PAI-1 antigen compared with corresponding values in lean controls. Blood t-PA antigen differed as well, yet basal endogenous fibrinolytic activity was decreased because of the high PAI-1 activity. The increased PAI-1 level was associated with increased levels of immunoreactive insulin (IRI). In diabetic subjects, coronary atherectomy specimens exhibited strong positive PAI-1 immunostaining, suggesting that in the diabetic vascular wall, intramural fibrinolytic activity is diminished. Using the oral glucose tolerance test, patients with significant stenosis confirmed by coronary angiography exhibited increased sigmaIRI, sigmaBS, sigmaIRI/sigmaBS, and IRI at 120 min compared to subjects without significant stenosis. IRI at 120 min was closely correlated with the severity of coronary artery disease. These results indicate that adipocyte overproduction of PAI-1 by insulin induces decreased endogenous fibrinolytic activity and contributes to the accelerated coronary macroangiopathy in hyperinsulinemic obese subjects with insulin resistance.
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PMID:Diminished fibrinolysis and thrombosis: clinical implications for accelerated atherosclerosis. 1085 61

A specific and robust immunoassay for the lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), platelet-activating factor acetylhydrolase, is described for the first time. The immunoassay was used to evaluate possible links between plasma Lp-PLA(2) levels and atherosclerosis risk amongst susceptible individuals. Such an investigation was important because Lp-PLA(2) participates in the oxidative modification of low density lipoprotein by cleaving oxidised phosphatidylcholines, generating lysophosphatidylcholine and oxidised free fatty acids. The majority of Lp-PLA(2) was found associated with LDL (approximately 80%) and, as expected, enzyme levels were significantly positively correlated to LDL cholesterol. Plasma Lp-PLA(2) levels were significantly elevated in patients with angiographically proven coronary artery disease (CAD) when compared with age-matched controls, even though LDL cholesterol levels did not differ significantly. Indeed, when included in a general linear model with LDL cholesterol and other risk factors, Lp-PLA(2) appeared to be an independent predictor of disease status. We propose, therefore, that plasma Lp-PLA(2) mass should be viewed as a potential novel risk factor for CAD that provides information related to but additional to traditional lipoprotein measurements.
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PMID:Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease. 1085 34

Several studies have demonstrated an increased level of plasma plasminogen activator inhibitor-1 (PAI-1) in patients with coronary artery disease (CAD). However, the concentration of PAI-1 in platelets, which accounts for more than 90% of the blood PAI-1, is unknown in these patients. The present study evaluated the concentrations of PAI-1 and several fibrinolytic factors in the plasma and platelets of patients with CAD and the serial changes in patients with acute myocardial infarction (AMI). All 72 subjects had coronary angiography and were divided into 3 groups: CAD(-) group without coronary artery stenosis or myocardial ischemia (n=20), CAD(+) group with either stable angina pectoris (n=18) or old myocardial infarction (n=12) with coronary artery stenosis, and the AMI group admitted within 24h of symptom onset who underwent successful percutaneous transluminal coronary angioplasty (n=22). The concentrations of plasma PAI-1, tissue plasminogen activator (t-PA), and t-PA x PAI-1 complex were similar in the CAD(-) and CAD(+) groups, but were greater on day 1 in the AMI group compared with the 2 CAD groups. There were no significant differences between the 3 groups in the plasma concentrations of thrombin antithrombin III complex (TAT), alpha2-plasmin inhibitor-plasmin complex (PIC), beta-thromboglobulin (beta-TG), and platelet factor 4 (PF-4). The platelet PAI-1 concentrations did not differ between the CAD(-) and CAD(+) groups, but was greater on day 1 in the AMI group compared to the CAD groups. The platelet beta-TG and PF-4 were similar between the 3 groups. In the AMI group, both the plasma and platelet PAI-1 concentrations were greater on day 1, but the plasma PAI-1 rapidly decreased by day 5 and remained low on day 28 compared with day 1. The platelet PAI-1 concentration gradually decreased by day 5 and was further decreased by day 28. The serial changes of the plasma t-PA and t-PA PAI-1 complex during the course of AMI were similar to those of the plasma PAI-1. A positive correlation was found between the plasma and platelet PAI-1 in all 72 patients, but not in the AMI group alone. These results suggest that the PAI-1 that has accumulated in platelets at the onset of AMI might be released in large amounts into the plasma, resulting in an increase in thrombus formation.
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PMID:Plasma and platelet plasminogen activator inhibitor-1 in patients with acute myocardial infarction. 1095 48

Abnormalities of coagulation or fibrinolysis play a role in the pathogenesis of coronary artery disease (CAD). Elevated plasma levels of fibrinogen, von Willebrand factor antigen, plasminogen activator inhibitor-1 and tissue-type plasminogen activator were reported to be predictive for reinfarction and death in patients with CAD. We investigated the risk for coronary re-events associated with 18 hemostatic and fibrinolytic parameters in a prospective study including 200 survivors of myocardial infarction (MI). During a 2-year follow-up, 37 patients suffered one of the following predefined re-events: fatal MI (n = 2), non-fatal MI (n = 5), percutaneous transluminal coronary angioplasty (n = 17) or coronary artery bypass grafting (n = 13). Low plasmin-alpha2-antiplasmin complex (PAP) plasma levels were associated with an up to fivefold (95% confidence interval, 1.6-15.3) increase in relative risk. The association between decreasing PAP levels and coronary re-events remained significant (P = 0.004) after correction for possible confounders using multiple logistic regression analysis. Our data indicate low PAP plasma levels to be associated with subsequent coronary events in patients with a history of MI.
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PMID:Hemostatic and fibrinolytic parameters in survivors of myocardial infarction: a low plasma level of plasmin-alpha2-antiplasmin complex is an independent predictor of coronary re-events. 1122 22


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