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)

Mutations in the plasminogen activator inhibitor-1 (PAI-1) gene, along with altered PAI-1 and tissue-type plasminogen activator (tPA) levels, have been implicated in stroke pathogenesis. We investigated the association of PAI-1 and tPA levels with stroke as a function of PAI-1 4G/5G and -844G/A genotypes, as well as the link between these PAI-1 gene variants and stroke risk, in a case-control study of 135 ischemic stroke patient, diagnosed according to clinical and radiologic findings and confirmed by computed tomography scan. Controls (n = 118) were age- and sex-matched and had no personal/family history of stroke. PAI-1 4G/5G and -844G/A genotyping were done by polymerase chain reaction-restriction fragment length polymorphism, and PAI-1 and tPA levels were measured by enzyme immunoassay. Significant elevation in PAI-1 and marked reduction in tPA levels were seen in stroke patients and were correlated with 4G/5G, but not with -844G/A, PAI-1 variants. Whereas the frequencies of 4G or -844A alleles were comparable between patients and controls, 4G/4G carriers had reduced risk of stroke compared with other genotypes (odds ratio [OR] = 0.54; 95% confidence interval [CI] = 0.31-0.95). The 4G/-844A haplotype also was more closely associated with reduced stroke risk (OR = 0.43; 95% CI = 0.20-0.97) than 5G/-844A or 4G/-844G haplotypes. Regression analysis demonstrated that 4G homozygosity (OR = 0.176), hypertension (OR = 6.288), and body mass index (OR = 1.325) were independent predictors of stroke. The protective effect of 4G allele against stroke suggests involvement of PAI-1 4G/5G polymorphism in stroke through a mechanism not related to fibrinolysis, possibly involving altered plaque stabilization, and/or through antagonism of tPA effects.
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PMID:Association of PAI-1 4G/5G and -844G/A gene polymorphism and changes in PAI-1/tPA levels in stroke: a case-control study. 1768 11

Although an atherogenic lipoprotein phenotype has been well recognized as an important predictor of cardiovascular disease, recent studies have demonstrated a number of additional lipid-related markers as emerging biomarkers to identify patients at risk for future coronary heart disease. Among them, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), seems to be a promising candidate that might be added to the clinical armamentarium for improved prediction of cardiovascular disease in the future. Of particular note, Lp-PLA(2) is the only enzyme that cleaves oxidized low-density lipoprotein (oxLDL) in the subendothelial space, with further generation of proinflammatory mediators such as lysophosphatidylcholine (LysoPC) and oxidized fatty acid (oxFA), thereby probably linking two important features of atherogenesis, namely oxidation of LDL and local inflammatory processes within the atherosclerotic plaque. This overview aims to summarize our current knowledge based on observations from recent experimental and clinical studies. Emphasis has been put on potential pathophysiological mechanisms of action and on the clinical relevance of Lp-PLA(2) in a wide variety of clinical settings, including apparently healthy individuals, patients with stable angina or acute coronary syndromes, after myocardial infarction, and with subclinical disease. Although a growing body of evidence from epidemiological and clinical studies suggests that Lp-PLA(2) may represent an independent and clinically relevant long-term risk marker for coronary heart disease and, probably, also for stroke, the role of this enzyme in the setting of the acute coronary syndrome remains to be established.
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PMID:Predicting the risk of cardiovascular disease: where does lipoprotein-associated phospholipase A(2) fit in? 1770 75

There is increasing evidence that modified phospholipid products of low density lipoprotein (LDL) oxidation mediate inflammatory processes within vulnerable atherosclerotic lesions. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is present in vulnerable plaque regions where it acts on phospholipid oxidation products to generate the pro-inflammatory lysophsopholipids and oxidized non-esterified fatty acids. This association together with identification of circulating Lp-PLA(2) levels as an independent predictor of cardiovascular disease provides a rationale for development of Lp-PLA(2) inhibitors as therapy for atherosclerosis. Here we report a systematic analysis of the effects of in vitro oxidation in the absence and presence of an Lp-PLA(2) inhibitor on the phosphatidylcholine (PC) composition of human LDL. Mass spectrometry identifies three classes of PC whose concentration is significantly enhanced during LDL oxidation. Of these, a series of molecules, represented by peaks in the m/z range 594-666 and identified as truncated PC oxidation products by accurate mass measurements using an LTQ Orbitrap mass spectrometer, are the predominant substrates for Lp-PLA(2). A second series of oxidation products, represented by peaks in the m/z range 746-830 and identified by LTQ Orbitrap analysis as non-truncated oxidized PCs, are quantitatively more abundant but are less efficient Lp-PLA(2) substrates. The major PC products of Lp-PLA(2), saturated and mono-unsaturated lyso-PC, constitute the third class. Mass spectrometric analysis confirms the presence of many of these PCs within human atherosclerotic lesions, suggesting that they could potentially be used as in vivo markers of atherosclerotic disease progression and response to Lp-PLA(2) inhibitor therapy.
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PMID:Electrospray ionization mass spectrometry identifies substrates and products of lipoprotein-associated phospholipase A2 in oxidized human low density lipoprotein. 1816 86

Plasminogen binding by bacteria is a virulence factor important for the entry and dissemination of bacteria in the body. A wide variety of bacteria bind plasminogen, including both organisms causing disease and components of the normal oral flora. The purpose of this study was to examine the characteristics of plasminogen binding by six clinical isolates of oral streptococci from both dental plaque and inflammatory lesions. All the strains bound plasminogen with approximately the same affinity, and binding was specific and lysine-dependent as evidenced by its inhibition by epsilon-aminocaproic acid. All of the test strains were capable of activating bound plasminogen to plasmin without the addition of a plasminogen activator, and subsequent analysis revealed the presence of streptokinase in all strains. However, the streptococci exhibited fibrinolytic activity only in the presence of plasminogen and this could be inhibited by the addition of epsilon-aminocaproic acid. SDS-PAGE and 2D gel electrophoresis coupled with plasminogen ligand blotting showed that only a subset of the total proteins (2-15) were involved in the binding of plasminogen. Partial identification of the binding proteins revealed that four glycolytic enzymes, enolase, phosphoglycerate kinase, glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate mutase, were predominant in binding plasminogen. The binding of plasminogen by bacteria from pus did not differ from that of the strains from supragingival plaque. The findings illustrate how apparently innocuous commensal bacteria are capable of utilizing a mechanism that is generally regarded as being of importance to pathogenicity and suggest an additional role of plasminogen binding.
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PMID:Plasminogen binding by oral streptococci from dental plaque and inflammatory lesions. 1831 38

Multiple cardiovascular biomarkers are associated with increased cardiovascular disease (CVD) risk. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be relatively unique in its high specificity for and the causal pathway of plaque inflammation. In both primary and secondary prevention study populations, Lp-PLA(2) was consistently associated with higher cardiovascular risk, and the risk estimate appears to be relatively unaffected by adjustment for conventional CVD risk factors. Risk ratios were similar, whether the mass concentration or activity of the enzyme was measured. The purpose of this article is to review the evidence for the clinical utility of Lp-PLA(2), both as a risk marker and as a risk factor involved in the causal pathway of plaque inflammation and the formation of rupture-prone plaque.
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PMID:Lipoprotein-associated phospholipase A2: a risk marker or a risk factor? 1854 67

In recent years, atherosclerosis has become recognized as an inflammatory disease whose activity can be assessed by circulating biomarkers. Along with C-reactive protein (CRP), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) may now be considered as a biomarker with sufficient accumulated evidence to support its application in clinical practice. Lp-PLA(2) is especially appealing because of its vascular specificity, which directly derives from its role in plaque pathophysiology. This article reviews the highlights of the >25 prospective epidemiologic studies now published on Lp-PLA(2) as a risk marker in primary or secondary prevention. These trials demonstrate generally consistent correlations between elevated Lp-PLA(2) levels and the increased risk for cardiovascular events, even after multivariable adjustment for traditional risk factors, with roughly a doubling of risk associated with upper quantile levels. Furthermore, Lp-PLA(2) as a risk predictor has been shown to be independent of and complementary to high-sensitivity CRP. These study results combined with recommendations from the American Heart Association/Centers for Disease Control (AHA/CDC) and the National Cholesterol Education Program III (NCEP III) suggest that Lp-PLA(2) might best be used in current clinical practice to refine risk prediction in those at intermediate cardiovascular risk. An increasingly prevalent group at intermediate risk shown to benefit from Lp-PLA(2) risk modification is the population with the cardiovascular metabolic syndrome, clinically identified as overweight patients with features of mixed dyslipidemia, dysglycemia, and hypertension. An additional application supported by these studies is further risk stratification of high- (often secondary-) risk patients into a group at very high risk, for whom a more aggressive target for low-density lipoprotein of <70 mg/dL (1 mg/dL = 0.02586 mmol/L) is now recommended as a reasonable therapeutic goal.
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PMID:Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention. 1854 68

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA(2) levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA(2) may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque.
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PMID:Identifying the vulnerable patient with rupture-prone plaque. 1854 69

Stroke is the second-leading cause of death worldwide and is a disabling disease of both older and younger adults. Stroke is also among the most highly preventable disorders because there are well-defined risk factors and preventatives. The establishment of new risk markers or factors for stroke risk assessment provides a new avenue for stroke prevention. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an enzyme that hydrolyzes oxidized phospholipids, releasing lysophosphatidylcholine, which has proinflammatory properties thought to be involved in the development of atherosclerosis and plaque rupture. In 2005, the Lp-PLA(2) blood test was approved by the US Food and Drug Administration (FDA) for assessing the risk of ischemic stroke and coronary artery disease. In epidemiologic studies, low-density lipoprotein cholesterol and other lipid factors have not been shown to be consistent predictors of stroke risk. Lp-PLA(2) measures, on the other hand, have shown a consistent association with stroke risk, conferring about a 2-fold increase in stroke occurrence. This relation has been studied in both first and recurrent stroke and is reviewed in this article. Importantly, a recent study has now shown that Lp-PLA(2) may increase the area under the curve beyond that of traditional cardiovascular risk factors and C-reactive protein. Therefore, Lp-PLA(2) determination may provide a pivotal opportunity to appropriately classify previously misclassified persons who are actually at high risk of stroke and in need of aggressive stroke intervention.
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PMID:Lipoprotein-associated phospholipase A2 and risk of stroke. 1854 70

Plaque rupture and subsequent embolism as well as thrombosis are major causes of acute myocardial infarction and stroke secondary to atherosclerosis. Pai-1, t-PA, TF and ET-1 are thrombosis- and thrombolysis-related factors which play important roles in thrombosis formation and plaque rupture. Since acute myocardial infarction and stroke are more likely to occur between 6 a.m. and 12 p.m. than at another time of the day, we studied the relationship between circadian rhythm and Pai-1, t-PA, TF and ET-1 in normal and atherosclerotic mice. Atherosclerosis was developed in apoE-/- mice fed a normal diet or a high cholesterol diet. The expression of Pai-1, t-PA, TF and ET-1 in the hearts of control C57BL/6J mice and atherosclerotic mice was measured by real-time RT-PCR at different Zeitgeber times (ZT) including ZT0, ZT4, ZT8, ZT10, ZT12, ZT14, ZT16 and ZT20. The expression of Pai-1, t-PA, TF and ET-1 peaked between ZT14 and ZT16 and bottomed at ZT10 in C57BL/6J mice. Their expression in apoE-/- mice fed a normal diet lost circadian rhythm. Their expression in apoE-/- mice fed a high cholesterol diet peaked at ZT4, indicating a reverse circadian rhythm. Our result indicates that circadian changes in the expression of Pai-1, t-PA, TF and ET-1 may be involved in the onset of myocardial infarction and stroke.
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PMID:Circadian rhythm disorder of thrombosis and thrombolysis-related gene expression in apolipoprotein E knock-out mice. 1863 67

Accurate imaging of atherosclerosis is a growing necessity for timely treatment of the disease. Magnetic resonance imaging (MRI) is a promising technique for plaque imaging. The goal of this study was to create polymeric particles of a small size with high loading of diethylenetriaminepentaacetic acid gadolinium (III) (Gd-DTPA) and demonstrate their usefulness for MRI. A water-in-oil-in-oil double emulsion solvent evaporation technique was used to encapsulate the MRI agent in a poly(lactide-co-glycolide) (PLGA) or polylactide-poly(ethylene glycol) (PLA-PEG) particle for the purpose of concentrating the agent at an imaging site. PLGA particles with two separate average sizes of 1.83 microm and 920 nm, and PLA-PEG particles with a mean diameter of 952 nm were created. Loading of up to 30 wt % Gd-DTPA was achieved, and in vitro release occurred over 5 h. PLGA particles had highly negative zeta potentials, whereas the particles incorporating PEG had zeta potentials closer to neutral. Cytotoxicity of the particles on human umbilical vein endothelial cells (HUVEC) was shown to be minimal. The ability of the polymeric contrast agent formulation to create contrast was similar to that of Gd-DTPA alone. These results demonstrate the possible utility of the contrast agent-loaded polymeric particles for plaque detection with MRI.
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PMID:Preparation and initial characterization of biodegradable particles containing gadolinium-DTPA contrast agent for enhanced MRI. 1879 5


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