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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of lipids in cell signaling and tissue physiology is demonstrated by the many CNS pathologies involving deregulated lipid metabolism. One such critical metabolic event is the activation of phospholipase A(2) (PLA(2)), which results in the hydrolysis of membrane phospholipids and the release of free fatty acids, including arachidonic acid, a precursor for essential cell-signaling eicosanoids. Reactive oxygen species (ROS, a product of arachidonic acid metabolism) react with cellular lipids to generate lipid peroxides, which are degraded to reactive aldehydes (oxidized phospholipid, 4-hydroxynonenal, and acrolein) that bind covalently to proteins, thereby altering their function and inducing cellular damage. Dissecting the contribution of PLA(2) to lipid peroxidation in CNS injury and disorders is a challenging proposition due to the multiple forms of PLA(2), the diverse sources of ROS, and the lack of specific PLA(2) inhibitors. In this review, we summarize the role of PLA(2) in CNS pathologies, including stroke, spinal cord injury, Alzheimer's, Parkinson's, Multiple sclerosis-Experimental autoimmune encephalomyelitis and Wallerian degeneration.
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PMID:Phospholipase A(2), reactive oxygen species, and lipid peroxidation in CNS pathologies. 1875 70

Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.
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PMID:Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. 1884 Nov 34

Basic and animal research implicate inflammatory mechanisms in the pathogenesis and progression of atherosclerosis, plaque rupture, thrombosis, and stroke. Inflammatory biomarkers, particularly high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2, have been identified as potential predictors of stroke risk and prognosis. Infections may also precipitate stroke. Medications, especially hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), reduce inflammatory marker levels independently of lipid effects, and the ability of statins to reduce coronary events and stroke correlates with their effect on inflammatory biomarkers. Vaccination against influenza may also reduce stroke risk. Determining whether reduction of biomarkers reduces risk of recurrent stroke, however, requires further study before inflammatory markers become a routine part of the evaluation of stroke patients.
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PMID:Inflammatory markers and stroke. 1909 Nov 70

Lipid accumulation in arteries induces vascular inflammation and atherosclerosis, the major cause of heart attack and stroke in humans. Extreme hyperlipidemia induced in mice and rabbits enables modeling many aspects of human atherosclerosis, but microscopic examination of plaques is possible only postmortem. Here we report that feeding adult zebrafish (Danio rerio) a high-cholesterol diet (HCD) resulted in hypercholesterolemia, remarkable lipoprotein oxidation, and fatty streak formation in the arteries. Feeding an HCD supplemented with a fluorescent cholesteryl ester to optically transparent fli1:EGFP zebrafish larvae in which endothelial cells express green fluorescent protein (GFP), and using confocal microscopy enabled monitoring vascular lipid accumulation and the endothelial cell layer disorganization and thickening in a live animal. The HCD feeding also increased leakage of a fluorescent dextran from the blood vessels. Administering ezetimibe significantly diminished the HCD-induced endothelial cell layer thickening and improved its barrier function. Feeding HCD to lyz:DsRed2 larvae in which macrophages and granulocytes express DsRed resulted in the accumulation of fluorescent myeloid cells in the vascular wall. Using a fluorogenic substrate for phospholipase A(2) (PLA(2)), we observed an increased vascular PLA(2) activity in live HCD-fed larvae compared to control larvae. Furthermore, by transplanting genetically modified murine cells into HCD-fed larvae, we demonstrated that toll-like receptor-4 was required for efficient in vivo lipid uptake by macrophages. These results suggest that the novel zebrafish model is suitable for studying temporal characteristics of certain inflammatory processes of early atherogenesis and the in vivo function of vascular cells.
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PMID:Vascular lipid accumulation, lipoprotein oxidation, and macrophage lipid uptake in hypercholesterolemic zebrafish. 1926 37

Chondroitin sulphate (CS) is a natural glycosaminoglycan present in the extracellular matrix and is formed by the 1-3 linkage of D-glucuronic acid to N-acetylgalactosamine. In chondrocytes, CS diminishes interleukin-1 beta(IL-1beta)-induced increases in p38 mitogen-activated protein kinase (p38MAPK) and signal-regulated kinase 1/2 (Erk1/2) phosphorylation, and decreases nuclear factor-kappaB (NF-kappaB) nuclear translocation and as a consequence, reduces the formation of pro-inflammatory cytokines, IL-1beta and TNF-alpha, and pro-inflammatory enzymes, such as phospholipase A2 (PLA2), cyclooxygenase 2 (COX-2) and nitric oxide synthase-2 (NOS-2). The mechanism of action of CS explains its beneficial effect on the cartilage, synovial membrane and subchondral bone. On the other hand, in vivo, CS given orally prevents hepatic NF-kappaB nuclear translocation, suggesting that systemic CS may elicit an anti-inflammatory effect in many tissues besides the articulation. There is preliminary evidence showing that in human beings, CS may be of benefit in other diseases where inflammation is an essential marker, such as psoriasis and atherosclerosis. The review of the literature suggest that CS might also be of interest for the treatment of other diseases with an inflammatory and/or autoimmune character, such as inflammatory bowel disease, degenerative diseases of the central nervous system and stroke, multiple sclerosis and other autoimmune diseases.
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PMID:Immunomodulatory and anti-inflammatory effects of chondroitin sulphate. 1952 43

Cardiovascular disease (CVD) is the number one cause of death in both adult men and women. It is evident that active inflammation in the coronary arteries remains a key factor in plaque instability and subsequent cardiovascular events. The current clinical dilemma is that inflammation can occur even in patients who are on statin therapy, as well as in patients with "normal" cholesterol levels. Because fully half of all patients with cardiovascular events have normal cholesterol levels, there is a need to re-evaluate the role of inflammatory factors and biomarkers to better identify patients at risk. Current risk factors include C-reactive protein, fibrinogen, and platelet activator inhibitor-1. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is another emerging risk factor. The weight of evidence suggests that this biomarker also promotes vascular inflammation. Patients with higher levels of Lp-PLA2 have higher rates of CVD and stroke. Measurement of Lp-PLA2 can improve the identification of people at increased risk for CVD, independent of cholesterol, or C-reactive protein level. Lp-PLA2 has been an innovative target of immunomodulation therapy, and clinical studies with specific inhibitors are in progress evaluating this approach for both atherosclerosis development and clinical event reduction.
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PMID:Lipoprotein-associated phospholipase A2: an independent predictor of cardiovascular risk and a novel target for immunomodulation therapy. 1969 Apr 73

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) contributes to atherosclerotic plaque instability and subsequent sudden coronary death. Statins are associated with decreased stroke risk and may improve stability of atherosclerotic plaques. The present study investigated the effect of simvastatin on expression of Lp-PLA(2) levels in atherosclerotic plaques and on Lp-PLA(2) activity in atherosclerotic aortas. Rabbits were a fed chow (control group) or a high-cholesterol diet (atherosclerosis group) for 12 weeks. An additional group on the high-cholesterol diet received simvastatin (5 mg/kg per day) for the last 4 weeks (simvastatin group). Lp-PLA(2) activity in plasma and atherosclerotic aortas was significantly higher in the atherosclerosis group than in the control group and, consistent with this, abundant Lp-PLA(2) protein was detected in plaques in the atherosclerosis group. Simvastatin significantly reduced Lp-PLA(2) activity in plasma and aorta tissue, and reduced Lp-PLA(2) protein level in atherosclerotic plaques. Whereas there was no significant difference in total atherosclerotic lesion area between simvastatin and atherosclerosis groups, simvastatin significantly reduced macrophage content, lipid retention and the intima/media ratio but increased the content of smooth muscle cells in atherosclerotic lesions. Thus, statin treatment markedly reduced Lp-PLA(2) in both plasma and atherosclerotic plaques. This was associated with attenuation of the local inflammatory response and improved plaque stability.
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PMID:Simvastatin reduces expression and activity of lipoprotein-associated phospholipase A(2) in the aorta of hypercholesterolaemic atherosclerotic rabbits. 1976 85

The inflammatory reaction is characterized by increased circulatory levels of various indicators of the severity of inflammation. The objective was to investigate the value of lipoprotein-associated phospholipase A2 (Lp-PLA2) in patients with noncardioembolic ischemic stroke and severe proinflammatory reaction. There were investigated prospectively Lp-PLA2 levels in sera from 47 patients with ischemic stroke and severe inflammatory reaction (32 men and 15 women, mean age 63 +/- 4.23 years) as compared to 38 patients with ischemic stroke without inflammatory reaction (21 men and 17 women, mean age 61 +/- 5.52 years) and 114 healthy elderly controls. Lp-PLA2 levels were assessed using the diaDexus PLAC test (a noncompetitive ELISA). Out of 47 patients with ischemic stroke and severe inflammatory reaction 36 presented Lp-PLA2 high levels (79%). Lp-PLA2 was detected with high levels in 17 out of 30 patients with ischemic stroke without inflammatory reaction (45%). Patients with ischemic stroke and severe inflammatory reaction presented Lp-PLA2 with high levels more frequently than the healthy controls (RR 12.1 [95% CI. 6.22 to 19.333], p<0.0001). Levels of Lp-PLA2 were higher in subjects who experienced a stroke as compared to controls. Lp-PLA2 is a strong predictor of recurrent stroke risk and of increased risk of dying. The determination of Lp-PLA2 should be used to predict patient risk of cardiovascular disease and stroke; it does provide additional risk of inflammation when used in conjunction with the traditional markers. Lp-PLA2 might be used not only for risk stratification of stroke patients, but also as target for treatment.
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PMID:Phospholipase A2 in patients with noncardioembolic ischemic stroke and severe inflammatory reaction. 1988 71

We sought to critically assess the role of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) in the prediction of cardiovascular events in primary and secondary prevention settings. The inclusion criteria for our study included population-based epidemiologic studies and the presence of clinical outcomes of interest, including atherosclerotic disease, coronary events, stroke, and cardiovascular death. Studies that lacked clinical outcomes or that involved animals were excluded. We included primary and secondary prevention studies of subjects in all ethnic groups and of either sex, with no age limitation. We searched MEDLINE, Google Scholar, and the Cochrane Library for studies with publication dates from January 1970 through July 2009, and we searched major cardiology meeting abstracts from 2000 through 2009. From each study, we used predictive ability-including relative risk, hazard ratio, odds ratio, and prevalence of high Lp-PLA(2) levels, with adjustment-along with baseline population characteristics.Of 33 studies that met our inclusion criteria, 30 showed a significant association between Lp-PLA(2) and cardiovascular events. Most of the studies had been adjusted for major Framingham risk factors and other variables that might influence the effect under question. After multivariate adjustments in cohort and nested case-control studies, increased levels of Lp-PLA(2) remained a significant predictor of cardiovascular events. The available body of evidence suggests that Lp-PLA(2) is a reliable marker of risk for cardiovascular events.
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PMID:Lipoprotein-associated phospholipase A2 as a novel risk marker for cardiovascular disease: a systematic review of the literature. 2020 Jun 24

Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and is modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cells, fatty streaks and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Serum lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA(2) measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA(2) are in development and show considerable promise. In addition to substantially inhibiting Lp-PLA(2), darapladib reduces the progression of the necrotic core volume of coronary artery atheromatous plaque.
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PMID:Lipoprotein-associated phospholipase A2: role in atherosclerosis and utility as a cardiovascular biomarker. 2022 20


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