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)

The ability of BCG-activated macrophages from C57BL/6J mice to lyse neoplastic targets was depressed by inhibitors of methyltransferase reactions (10(-4) M adenosine, 10(-5) M EHNA, and 10(-4) M L-homocysteine or 10(-5) M DZA). Binding of P815 mastocytoma targets to BCG-activated macrophages, which has been shown to be a necessary event in cytolysis of those targets, was also inhibited by adenosine, EHNA, and L-homocysteine or by DZA at the above concentrations. Inhibition of binding was obtained when macrophages were pretreated with the inhibitors, whereas pretreatment of targets with the inhibitors did not alter binding. The inhibitors were not toxic to the macrophages, as judged by morphology and viability of the macrophage cultures as well as by ability of macrophages to bind antibody-coated P815 targets or to secrete plasminogen activator. The inhibitors, at concentrations that inhibited cytolysis and binding, also depressed one type of S-adenosyl-L-methionine-mediated methylation reaction (protein carboxy-O-methylation) in BCG macrophages. The data suggest that transmethylation reactions are essential for the ability of BCG activated murine macrophages to bind and, hence, to destroy P815 tumor cells.
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PMID:The role of transmethylation reactions in regulating the binding of BCG-activated murine macrophages to neoplastic target cells. 724 Jul 42

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.
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PMID:Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. 778 64

Homocystinuria is a rare inherited metabolic disease. Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients. It has been suggested that mild homocysteinemia could be a risk factor for vascular disease. We have therefore measured total plasma homocysteine (HCy) concentrations by radioisotopic assay in 50 subjects with venous or arterial thrombosis and studied the relationship between HCy, coagulation and fibrinolytic parameters. Values were considered abnormal if they were higher than 2.7 standard deviations (SD) above the mean, i.e., 14.1 mmol/l. Thus, eighteen of the 50 patients with thrombosis were classified in the hyperhomocysteinemia group. Nine of these subjects had only this isolated risk factor. No correlations were found between HCy and antithrombin III, protein C, protein S and plasminogen levels, or plasma plasminogen activator inhibitor activity. Nevertheless, the correlation between tissue-plasminogen activator antigen and total plasma HCy was significant (r = 0.61, p < 0.001). Increased homocysteinemia seems to be a risk factor for thrombotic events especially knowing that HCy presents a direct cytotoxic effect. Vitamin therapy, already used in homozygote homocystinuric patients, might be beneficial in the prevention of thromboembolic disease in heterozygous patients.
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PMID:Elevated total plasma homocysteine, a risk factor for thrombosis. Relation to coagulation and fibrinolytic parameters. 832 83

Endothelial cells impart thromboresistance to the blood vessel wall. As modulators of fibrinolytic activity, these cells synthesize and secrete tissue plasminogen activator (t-PA) as well as its physiologic inhibitor, plasminogen activator inhibitor-1. In addition, endothelial cells support membrane-associated assembly of plasminogen and tissue plasminogen activator. Recently, an M(r) approximately 40,000 protein expressed on endothelial cells has been shown to interact noncompetitively through disparate mechanisms with both t-PA and plasminogen, suggesting trimolecular assembly of enzyme, substrate, and receptor (Hajjar, K. A. 1991. J. Biol. Chem. 266:21962-21970). In the present study, treatment of cultured endothelial cells with DL-homocysteine was specifically associated with a selective reduction in cellular binding sites for t-PA. This 65% decrease in binding was associated with a 60% decrease in cell-associated t-PA activity. No change in affinity for t-PA or plasminogen or in the maximal number of binding sites for plasminogen was observed. Matrix-associated t-PA binding sites were not affected. These data suggest a new mechanism whereby homocysteine may perturb endothelial cell function, thus promoting a prothrombotic state at the surface of the blood vessel wall.
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PMID:Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. 839 Apr 92

Over 200 risk factors for cardiovascular disease (CVD) have now been identified. Among these, the three most important are (1) abnormal lipids, including the fact that there are more than 15 types of cholesterol-containing lipoproteins and four different types of triglyceride-rich particles, some of which are very atherogenic, (2) high blood pressure, and (3) cigarette smoking. In addition, many other factors including diabetes, haemostatic factors such as fibrinogen, factor VII, plasminogen activator inhibitors, and new factors such as apolipoprotein E4 and homocysteine, are known to increase the risk of developing clinical CVD. A low risk for CVD requires that these various factors are present in the circulation in the correct proportions. Two simple tests for determining plasma lipid levels can be used to identify those individuals with an atherogenic lipid profile and who are, therefore, at increased risk for CVD. Firstly, the ratio of total cholesterol to high density cholesterol (HDL cholesterol) should be determined, followed by measurement of plasma triglyceride concentrations. This will allow differentiation of whether the low density lipoproteins (LDL), HDL cholesterol or triglyceride-rich particles such as the small dense beta-very low density lipoproteins (VLDL) are the major cause for concern. Once identified, those individuals with a high lipid risk profile should be treated before, rather than after, experiencing coronary heart disease (CHD).
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PMID:Lipids, risk factors and ischaemic heart disease. 883 10

Prinzmetal's variant angina, primarily a vasospastic disease, is a glaring example of the gaps in our knowledge regarding the etiology of coronary heart disease. Half of all patients with coronary heart disease do not have any of the established coronary risk factors. Prinzmetal's variant angina, syndrome X, coronary embolization, and congenital coronary anomalies, are a few examples of conditions that may not be associated with established risk factors. New risk factors that are emerging in an attempt to establish an etiology in this group of patients are homocysteine plasma fibrinogen, estrogen-deficiency lipoprotein (a), C-reactive protein, Chlamydia pneumoniae, factor VII endogenous tissue plasminogen, and endogenous plasminogen activator/inhibitor type I. The battle against cardiovascular disease continues!
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PMID:Fifty percent of patients with coronary artery disease do not have any of the conventional risk factors. 957 51

Recent evidence indicates a potential role for the plasmin/plasminogen activator system in the prevention of atherosclerotic vascular disease. Fibrin deposition is a common histologic feature of the tissues of mice that are genetically deficient in one or more key components of the fibrinolytic system. Cell surface receptors may support fibrinolytic surveillance in both intravascular and extravascular locations by stimulating the efficiency plasmin generation and by protecting plasmin from its inhibitors. In vitro studies suggest that the endothelial cell receptor, annexin II, which independently binds both plasminogen and t-PA, could play a key role in the process. Binding of plasminogen to annexin II is specifically inhibited in the presence of excess concentrations of the atherogenic LDL-like particle Lp(a). Similarly, t-PA binding to annexin II is blocked by homocysteine, a sulfhydryl-containing amino acid that is associated with atherogenesis and that directly derivatizes the t-PA binding domain of annexin II. Elucidation of the precise role of annexin II in fibrinolytic surveillance, however, will await in vivo study.
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PMID:Modulation of annexin II by homocysteine: implications for atherothrombosis. 980 20

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

Several prospective studies have demonstrated a direct association between C-reactive protein (CRP) levels and the risks of developing cardiovascular disease. Few studies, however, have explored the interrelations between CRP levels and other risk factors for cardiovascular disease. We evaluated the relation of CRP with several cardiovascular risk factors in a cross-sectional survey of 1,172 apparently healthy men. There were significant positive associations between CRP levels and age, number of cigarettes smoked per day, body mass index, systolic and diastolic blood pressure, total cholesterol, triglycerides, lipoprotein(a), apolipoprotein B, tissue-type plasminogen activator antigen, D-dimers, total homocysteine, and fibrinogen (all p values <0.05). Significant inverse associations were observed for exercise frequency, high-density lipoprotein cholesterol, and apolipoprotein A-I and A-II (all p values <0.02). In multivariate analysis, age, smoking status, and serum levels of tissue-type plasminogen activator antigen, fibrinogen, lipoprotein(a), and total homocysteine were independent correlates of CRP levels. Finally, in an analysis controlled either for all the independent correlates or for several usual risk factors, we observed progressive increases in levels of CRP with increasing prevalence of risk factors (p for trend <0.001 for independent correlates and <0.01 for usual risk factors). In conclusion, in a large cohort of apparently healthy men, CRP levels were associated with several cardiovascular risk factors. These data are compatible with the hypothesis that CRP levels may be a marker for preclinical cardiovascular disease.
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PMID:Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men. 1056 56

Homocysteine (HC) is a highly reactive thiol intermediate in amino acid metabolism, which can modify the function of endothelial cells in a myriad of ways. In vitro, homocysteine can inhibit the thromboresistance properties of the endothelial cell by induction of procoagulant factors, inactivation of natural anticoagulant systems, and suppression of vasodilatory and platelet-modulating factors. HC also inhibits the fibrinolytic system by impairing the ability of the endothelial cell to bind tissue plasminogen activator (t-PA), by interacting directly with the t-PA binding "tail" domain of its endothelial cell receptor, annexin II. Moreover, HC influences endothelial cell gene expression as exemplified by induction of the elongation factor-1 family of polypeptides, which promote polypeptide chain elongation during mRNA translation. Induction of EF-1 subunits alpha, beta, gamma and delta by homocysteine is associated with increased turnover of at least one free thiol-containing protein, suggesting that up-regulation of these subunits may represent a mechanism for replacement of damaged or modified proteins. A more complete understanding of the diverse effects of homocysteine on endothelial cell function may provide important clues to the precise role homocysteine may play in the initiation and progression of vascular disease.
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PMID:Inhibition of endothelial cell thromboresistance by homocysteine. 1072 10


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