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)

Secretory phospholipase A(2) (PLA(2)) can be proatherogenic both in the circulation and in the arterial wall. In blood plasma, PLA(2) can modify the circulating lipoproteins and so induce formation of small dense LDL particles, which are associated with increased risk for cardiovascular disease. In the arterial wall, PLA(2) can hydrolyze lipoproteins. The PLA(2)-modified lipoproteins bind tightly to extracellular proteoglycans, which may lead to their enhanced retention in the arterial wall. The modified lipoproteins may also aggregate and fuse, which can lead to accumulation of their lipids within the extracellular matrix. The PLA(2)-modified particles are more susceptible to further modifications by other enzymes and agents and can be taken up by macrophages, leading to accumulation of intracellular lipids. In addition, lysophospholipids and free fatty acids, the hydrolysis products of PLA(2), promote atherogenesis. Thus, these lipid mediators can be carried, either by the PLA(2)-modified lipoproteins themselves or by albumin, into the arterial cells, which then undergo functional alterations. This may, in turn, lead to specific changes in the extracellular matrix, which increase the retention and accumulation of lipoproteins within the matrix. In the present article, we discuss the possible actions of PLA(2) enzymes, especially PLA(2)-IIA, in the arterial wall during atherogenesis.
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PMID:Phospholipase A(2) in vascular disease. 1150 45

An association between an increase in plasminogen activator inhibitor type 1 (PAI-1) and obesity, and also between elevated levels of PAI-1 and the presence of PAI-1 promoter 4G allele has been described in adults and can contribute to increased risk of cardiovascular disease. It has also been suggested that in adults a decrease in adiposity has beneficial effects on the haemostatic system. However, less information is available regarding adiposity and fibrinolysis in children. The aim of the present study is to evaluate the effect of weight loss and the influence of the PAI-1 promoter 4G/5G genotype on the fibrinolytic system and lipid parameters in obese children. The clinical groups included 102 obese children and 105 controls of similar age and sex distribution. A significant decrease in fibrinolytic activity due to a significant increase in PAI-1 antigen and activity levels was observed in the obese children in comparison with the control group. In obese children, no significant differences in PAI-1 levels between the PAI-1 4G/5G genotypes were obtained. A significant correlation was observed between PAI-1 antigenic and functional levels and body mass index (BMI), as well as between PAI-1 levels and both triglyceride and insulin levels. No correlation between PAI-1 levels and either cholesterol or glucose levels was observed. After a three-month period of treatment to reduce weight, an increase in fibrinolytic activity due to a decrease in PAI- levels was observed in the obese children who had reduced their BMI in comparison with the group of obese children who did not show a decrease in their BMI. No significant differences between the two groups with respect to the variations in tissue type plasminogen activator and fibrinogen levels were obtained after three months of intervention to reduce weight. A significant correlation was observed between variations in BMI and variations in PAI-1 levels, and a significant inverse correlation was also observed between previous PAI-1 levels and variation in PAI-1 levels. Therefore, the largest decrease in PAI-1 levels was observed in the obese children with the highest previous PAI-1 levels. In conclusion, a decrease in BMI in obese children shows a favourable effect on the fibrinolytic system due to a decrease in PAI-1 levels. However, no influence of 4G/5G genotype on PAI-1 levels was observed.
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PMID:Plasma PAI-1 levels in obese children--effect of weight loss and influence of PAI-1 promoter 4G/5G genotype. 1152 17

Plasminogen activator inhibitor type-1 (PAI-1) is known to contribute to thrombus formation and to the development and the clinical course of acute and chronic cardiovascular disease, as well as of other arterial and venous thromboembolic diseases. Recently, an important role of elevated pretreatment levels of PAI-1 for failure of thrombolytic therapy of acute myocardial infarction has been discussed. PAI-1 plasma levels depend on the one hand on gene regulation but are related on the other hand to known risk factors of atherosclerosis like insulin resistance, diabetes or hypertriglyceridemia, respectively. Furthermore, an activated renin-angiotensin-aldosterone system (RAAS) significantly contributes to the upregulation of PAI-1 concentration via a receptor-mediated mechanism. In accordance to the known mechanisms of regulation of PAI-1 plasma levels, the use of specific agents like antidiabetic drugs, fibrates, statins, ACE inhibitors and angiotensin II type-1 receptor-blockers may contribute to the downregulation of circulating PAI-1 and, therefore, increase the fibrinolytic capacity and consecutively counteract the thrombotic tendency. To further improve the efficacy of thrombolytic therapy, a PAI-1 resistant variant of t-PA, TNK-t-PA, has been developed and is now available for acute myocardial infarction.
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PMID:Plasminogen activator inhibitor type-1 in cardiovascular disease. Status report 2001. 1156 64

The study was carried out in a group of 285 children and adolescents aged 4-20 yrs. Children were divided according to their main disease: group with obesity, obesity and coexisting hypertension, hypertension and diabetes. Each group was divided into children with positive or negative family history of cardiovascular diseases. We assessed routine lipid parameters, body mass index and new atherosclerosis risk factors: lipoprotein (a), apolipoproteins A-I and B, homocysteine, fibrinogen, t-PA and PAI-1. Positive family history of cardiovascular diseases was found in 28% families, and in 8% families it was premature cardiovascular disease. In 48% children we found hypertension in family. Children with positive family history had significantly higher body mass index (25.4 vs 23.8 kg/m2). In the group with obesity and hypertension we found significantly higher cholesterol (182 vs 160 mg/dl) and LDL-cholesterol level (114 vs 93 mg/dl). Lipoprotein(a) level was significantly higher in children with positive family history (38 vs 28 mg/dl). Significant differencies were also found in apolipoprotein B level (90 vs 84 mg/dl). In logistic regression analysis only BMI and lipoprotein(a) were significant in predicting future cardiovascular events in children. Obese, hypertensive and diabetic children often come from families with cardiovascular diseases. Hypertension is the most often prevalent atherosclerosis risk factor in families. Children with positive family history of cardiovascular diseases have significantly higher body mass index. Out of new atherosclerosis risk factors lipoprotein(a) and apolipoprotein B may have real value in predicting future cardiovascular disease in the child. The aim of the study was to compare obese, hypertensive and diabetic children with positive and negative family history of cardiovascular diseases. In the work we have tried to find which of the new atherosclerosis risk factors may have the real value in predicting future cardiovascular events in children already predisposed to atherosclerosis.
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PMID:[Correlation between body mass index, lipoprotein (a) level and positive family history of cardiovascular diseases in children and adolescents with obesity, hypertension and diabetes]. 1199 45

In Italy (130,000 new strokes in the general population per year) ischemic stroke is the third cause of death, after cardiovascular disease and neoplastic disease with a prevalence of 6.5%. Different physicians are involved in the emergent evaluation and treatment of the acute ischemic stroke. As other acute events, the initial evaluation must be addressed to assess the patient's airway and breath-ing and cardiocirculatory conditions. The neurological examination must not be exhaustive and it should be completed in 5-10 minutes and a particular attention should be given to clinical findings leading to the suspect of an intracranial hemorrhages. A plain CT scan of the brain is the most important initial diagnostic study. Emergency therapy must be mainly directed to the correction of hypovolemia, hypoxia and the treatment of severe hypertension, hypoglycemia, intracranial hypertension and seizures. The goal is to achieve and to maintain an adequate cerebral perfusion by lowering the intracranial pressure (treating the cerebral oedema) and by increasing the mean arterial pressure, with an appropriate volemic expansion and/or with inotropic or vasopressor drugs. The thrombolytic therapy with intravenous recombinant tessutal plasminogen activator (r-TPA) when not specifically contraindicated, is recommended within 3 hours of onset of ischemic stroke. The benefit of intravenous r-TPA for acute ischemic stroke beyond 3 hours from the onset has never been proved.
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PMID:Stroke patients, what to do and what to avoid. 1202 99

It is well established that inflammation is an integral feature of atherosclerosis and of the cardiovascular diseases which it underlies. Oxidative stress is also recognized as a key actor in atherogenesis, in which it is closely associated with the inflammatory response and bioactive lipid formation. Several bioactive lipids have been identified in the atherosclerotic plaque, including the potent inflammatory mediator platelet activating factor (PAF), PAF-like lipids, oxidised phospholipids (oxPL) and lysophosphatidylcholine (lyso-PC). Recent evidence has established a central role of two phospholipases (PL) in atherogenesis, the non-pancreatic Type II secretory phospholipase A(2) (sPLA(2)) and the lipoprotein-associated PLA(2)-alternatively termed as PAF-acetylhydrolase (PAF-AH). sPLA(2) is calcium-dependent and hydrolyses the sn-2 acyl group of glycerophospholipids of lipoproteins and cell membranes to produce lyso-PC and free fatty acids. It is also implicated in isoprostane production from oxPL. sPLA(2) is an acute phase reactant, which is upregulated by inflammatory cytokines and may represent a new independent risk factor for coronary heart disease. In contrast to sPLA(2), PAF-AH is calcium-independent and is specific for short acyl groups at the sn-2 position of the phospholipid substrate and with the exception of PAF, can equally hydrolyze oxPL to generate lyso-PC and oxidized fatty acids. Thus PAF-AH plays a key role in the degradation of proinflammatory oxPL and in the generation of lyso-PC and oxidized fatty acids. PAF-AH equally can also hydrolyze short-chain diacylglycerols, triacylglycerols, and acetylated alkanols, and displays a PLA(1) activity. Whereas sPLA(2) may represent a new independent risk factor for coronary artery disease, the potential relevance of PAF-AH to atherosclerosis remains the subject of debate, and recent results suggest that the potential role of the LDL-associated PAF-AH in atherogenesis may be distinct to that of the HDL-associated enzyme. This review is focused on the main structural and catalytic features of plasma PAF-AH, on the association of the enzyme with distinct lipoprotein particle subspecies, on its cellular sources, and finally on the potential significance of this lipoprotein-associated PLA(2) in cardiovascular disease.
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PMID:Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase. 1257 64

While there is indisputable evidence supporting the beneficial role of aerobic exercise in reducing cardiovascular risk factors, there are few dose-response studies of this relationship. Increasingly, it is thought that the cardiovascular benefits of exercise are significantly influenced by adaptations within skeletal muscle and its vasculature. However, little is known about the molecular mechanisms underlying these adaptations. To address this need, we initiated a study utilizing longitudinal, microarray-based gene expression profiling of serial skeletal muscle biopsies obtained from the study of targeted risk reduction intervention through defined exercise (STRRIDE). STRRIDE participants were overweight and exhibited symptoms characteristic of the metabolic syndrome that typically precedes type II diabetes such as insulin resistance, abnormal lipids and glucose intolerance. Expression data were statistically filtered and sorted into exercise training-responsive clusters based on gene product knowledge. One such cluster included genes that promote the degradation of fibrin clots such as tissue plasminogen activator (t-PA), connective tissue activation peptide III (CTAP III) and tetranectin. The fibrinolytic activity and protein levels of tetranectin, and t-PA and its endogenous inhibitor PAI-1, were subsequently shown to change significantly in both skeletal muscle and serum in response to exercise training. Our data show that the rigors of exercise directly induce fibrinolytic genes and protein cascades, both within muscle, and in the systemic circulation. This finding is particularly significant given that the metabolic syndrome is an independent risk factor for peripheral vascular disease and thrombotic events within the heart and brain. We conclude that aerobic exercise training induces both local and systemic changes in fibrinolysis and vascular homeostasis that are probably protective against cardiovascular disease.
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PMID:Skeletal muscle dictates the fibrinolytic state after exercise training in overweight men with characteristics of metabolic syndrome. 1261 18

Inflammation and thrombosis are important mechanisms in cardiovascular disease, as illustrated by the consistent association between inflammatory and hemostatic variables and the risk of cardiovascular events in epidemiological studies. However, the relationship between plasma concentrations of inflammatory and hemostatic markers and the severity of atherosclerosis is not yet well studied. We have evaluated 325 men and 370 women of 60 years, participating in the Danish Glostrup study. We diagnosed atherosclerosis by ultrasonographic measurement of intima-media thickness (IMT) of the right carotid artery and the assessment of plaque occurrence. Plasma samples were analyzed for the concentration of C-reactive protein (CRP), fibrinogen, d-dimer, plasminogen activator inhibitor type-1 (PAI-1) antigen and activity, tissue-type plasminogen activator (t-PA) antigen and activity, factor VII (FVII) antigen, FVII coagulant activity (FVII:C) and activated FVII (FVIIa). DNA variations were determined for fibrinogen, PAI-1, t-PA, FVII, factor XIII and methylene tetrahydrofolate reductase (MTHFR). Subjects with high IMT (upper 10% of distribution, n = 63) had higher CRP levels [2.2 mg L-1 (SE 0.3)] than subjects with IMT in the lowest tertile (n = 217) [1.7 mg L-1 (SE 0.1), P = 0.04], whereas there was no association between the hemostatic variables and IMT. There was an association between fibrinogen and d-dimer concentrations and number of plaques (P < 0.01), whereas there were no associations between CRP and the other hemostatic variables and the number of plaques. Genetic variation in the t-PA and MTHFR gene was associated with IMT. In conclusion, in the Glostrup population study, thrombosis and inflammation are associated with the severity of atherosclerosis, as reflected by IMT and plaque occurrence.
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PMID:Inflammation, thrombosis and atherosclerosis: results of the Glostrup study. 1287 60

There is growing evidence that stress contributes to cardiovascular disease. Chronic stress contributes to the atherosclerotic process through increased allostatic load, which is mediated by the neuroendocrine and immune systems (sympathetic nervous system and hypothalamus-pituitary adrenal axis) and related chronic risk factors (insulin resistance syndrome, hypertension, diabetes, and hyperlipidemia). In addition, acute stress can trigger cardiovascular events predominantly through sympathetic nervous activation and potentiation of acute risk factors (blood pressure increase, endothelial cell dysfunction, increased blood viscosity, and platelet and hemostatic activation). Earthquakes provide a good example of naturally occurring acute and chronic stress, and in this review we focus mainly on the effects of the Hanshin-Awaji earthquake on the cardiovascular system. The Hanshin-Awaji earthquake resulted in a 3-fold increase of myocardial infarctions in people living close to the epicenter, particularly in women, with most of the increase occurring in nighttime-onset events. There was also a near doubling in the frequency of strokes. These effects may be mediated by changes in hemostatic factors, as demonstrated by an increase of D-dimer, von Willebrand factor, and tissue-type plasminogen activator (tPA) antigen. Blood pressure also increased after the earthquake, and was prolonged for several weeks in patients with microalbuminuria.
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PMID:Disasters and the heart: a review of the effects of earthquake-induced stress on cardiovascular disease. 1288 26

Tissue-type plasminogen activator (tPA) plays a key role in thrombus dissolution and plasma levels of tPA have been associated with cardiovascular disease. We have previously resequenced regulatory and coding regions of the human tPA gene (PLAT) and identified eight single-nucleotide polymorphisms (SNPs). In a small experimental study, four common variants were associated with invasively determined vascular tPA release rates. The aim of the present study was to investigate whether there is an association between genetic variants at this locus and plasma levels of tPA. To this end, 240 Swedish individuals without cardiovascular disease were typed for the eight SNPs and an Alu insertion polymorphism at the PLAT locus, as well as for a polymorphism in the plasminogen activator inhibitor type 1 (PAI-1) promoter (PAI-1 -675 4G>5G). Stepwise regression analysis, with established predictors of plasma tPA including plasma PAI-1 and genetic variants, showed that neither genotypes nor haplotypes were major contributors to plasma tPA. The results also showed that the level of linkage disequilibrium was high at the PLAT locus, as demonstrated by the fact that only three haplotypes had a frequency above 5%. In conclusion, in the present study neither genetic variation at the PLAT locus nor the PAI-1 -675 4G>5G polymorphism was strong predictors of plasma tPA levels, which suggests that variations in other genes contribute to the heritability of this phenotype. The results also show that three haplotypes at the PLAT locus accounted for nearly 90% of the chromosomes and that they could be defined by typing only two SNPs.
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PMID:Genetic variation at the human tissue-type plasminogen activator (tPA) locus: haplotypes and analysis of association to plasma levels of tPA. 1289 81


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