Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type IIA secretory phospholipase A(2) (sPLA(2)) is an acute-phase reactant that plays a role in atherogenesis and is expressed in atherosclerotic arterial walls displaying inflammatory features. This generates a relevant question addressing the biological effects of this enzyme on monocytic cells, in view of the role of these cells in the inflammatory process associated with atherosclerosis. sPLA(2) produced a mild activation of the p42 mitogen-activated protein module of the mitogen-activated protein kinase (MAPK) cascade and a prominent activation of c-Jun N-terminal kinase in THP-1 monocytes. This activation showed both an early and a late peak, different from that elicited by tumor necrosis factor-alpha (TNF-alpha), which only showed the first peak. This was accompanied by activation of arachidonate metabolism, as judged from both the activation of the cytosolic phospholipase A(2) (cPLA(2)) and the induction of cyclooxygenase-2 (COX-2) expression. sPLA(2) also elicited the production of monocyte chemoattractant protein-1 (MCP-1) and showed a synergistic effect with TNF-alpha on both COX-2 induction and MCP-1 production. sPLA(2) upregulated the expression of Fas ligand at the cell surface, but it did not influence Fas expression nor cell survival of monocytes. In summary, these data indicate that some of the atherogenic effects of sPLA(2) can be exerted by engagement of an sPLA(2)-binding structure on monocytic cells, most probably the M-type receptor for sPLA(2), which produces the activation of the MAPK cascade, induces a proinflammatory phenotype, and upregulates the cell surface expression of Fas ligand.
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PMID:Secretory phospholipase A(2) elicits proinflammatory changes and upregulates the surface expression of fas ligand in monocytic cells: potential relevance for atherogenesis. 1178 16

Several studies have shown that humoral markers of inflammation and endothelial dysfunction are predictive of macrovascular events, and correlated with indirect measures of adiposity and insulin action, thus providing a possible link between obesity, insulin resistance and atherosclerosis. We examined the relationship between humoral markers of inflammation and endothelial dysfunction and direct measures of adiposity and insulin action in Pima Indians, a population with a very high prevalence of obesity and insulin resistance, but a relatively low propensity for atherosclerotic disease. Fasting plasma concentrations of the inflammatory markers C-reactive protein (CRP), secretory phospholipase A2 (sPLA2) and soluble intercellular adhesion molecule-1 (sICAM-1) and of the endothelial markers E-selectin and von Willebrand factor (vWF) were measured in 32 non-diabetic Pima Indians (18 M/14 F, age 27+/-1 years) in whom percent body fat and insulin-stimulated glucose disposal (M) were assessed by DEXA and a hyperinsulinemic clamp, respectively. CRP, sPLA2, and sICAM-1 were all positively correlated with percent body fat (r=0.71, 0.57, and 0.51, all P<0.01). E-selectin and vWF were not correlated with percent body fat, but were negatively correlated with M (r= -0.65 and -0.46, both P<0.001) and positively correlated with CRP (r=0.46, and 0.33, both P<0.05). These findings indicate that humoral markers of inflammation increase with increasing adiposity in Pima Indians whereas humoral markers of endothelial dysfunction increase primarily in proportion to the degree of insulin resistance and inflammation. Thus, obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction, respectively, even in an obesity- and diabetes-prone population with relatively low propensity for atherosclerosis.
Atherosclerosis 2002 Mar
PMID:Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians. 1188 37

Freshly solubilized A beta peptides synergistically increase the magnitude of the constriction induced by endothelin-1 (ET-1), via the activation of a pro-inflammatory pathway. We report that mevinolin and mevastatin, two inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are able to completely abolish the vasoactive properties of A beta in rat aortae. Mevinolin also appears to oppose the increased vascular reactivity to ET-1 induced by interleukin 1-beta and phospholipase A(2) suggesting that statins display some anti-inflammatory properties. We show that freshly solubilized A beta stimulates prostaglandin E(2) and F(2 alpha) production (by 6 and 3.6 times, respectively) in isolated rat aortae and that mevinolin completely antagonizes this effect confirming the anti-inflammatory action of mevinolin ex vivo in rat aortae. In addition, we observed that A beta vasoactivity is not mediated nor modulated by mevalonic acid suggesting that the anti-inflammatory action of the statins are not related to an inhibition of HMG-CoA reductase activity. Differentiated human neuroblastoma cells (IMR32) were used to assess the neurotoxic effect of pre-aggregated A beta by quantifying the release of lactate dehydrogenase (LDH) in the cell culture medium. A beta appears to enhance LDH release by 30% in IMR32 cells, an effect that can be completely opposed by mevastatin. Taken together these data show that statins can antagonize the effect of A beta in different assays and provide new clues to understand the prophylactic action of the statins against Alzheimer's disease.
Atherosclerosis 2002 Apr
PMID:Statins inhibit A beta-neurotoxicity in vitro and A beta-induced vasoconstriction and inflammation in rat aortae. 1188 11

In an effort to understand the role of key eicosanoid-forming enzymes in the activation of peroxisome proliferator-activated receptor (PPAR), this study was designed to evaluate the possible contributions of cytosolic phospholipase A(2) (cPLA(2)) and group IIA secretory phospholipase A(2) (sPLA(2)) in the regulation of PPAR-mediated gene transcription in a human hepatoma cell line (HepG2). The HepG2 cells express both PPAR-alpha and -gamma but not PPAR-beta. Overexpression of cPLA(2), but not group IIA sPLA(2) in the HepG2 cells, caused a significantly increased PPAR-alpha/gamma-mediated reporter activity. Antisense inhibition of cPLA(2) resulted in a significantly decreased PPAR-alpha/gamma activity. The PPAR-alpha/gamma-induced gene transcription in the HepG2 cells was inhibited by the cPLA(2) inhibitors methyl arachidonyl fluorophosphonate and arachidonyltrifluoromethyl ketone, but not by the sPLA(2) inhibitor LY311727. The expression of PPAR-alpha-mediated endogenous gene apolipoprotein A-II was increased in cells with overexpression of cPLA(2), decreased in cells with antisense inhibition of cPLA(2), but unaltered in cells with overexpression of group IIA sPLA(2). The above results demonstrated an important role of cPLA(2), but not group IIA sPLA(2) in the control of PPAR activation. The cPLA(2)-mediated PPAR activation was likely mediated by arachidonic acid and prostaglandin E(2). This study reveals a novel intracellular function of cPLA(2) in PPAR activation in HepG2 cells. The cPLA(2) thus may represent a potential therapeutic target for the control of PPAR-related liver and metabolic disorders such as obesity, lipid metabolic disorders, diabetes mellitus, and atherosclerosis.
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PMID:85-kDa cPLA(2) plays a critical role in PPAR-mediated gene transcription in human hepatoma cells. 1189 17

Cardiovascular disease is the leading cause of death in most industrialized countries. However, the diagnosis and management of coronary heart disease is far from optimal. Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase, is an enzyme that hydrolyses oxidized phospholipids and is primarily associated with low-density lipoprotein. Discussed in this review is the accumulating evidence supporting the view that Lp-PLA2 is a potential biomarker of coronary heart disease and plays and an important proinflammatory role in the progression of atherosclerosis. A new ELISA method for the quantitative measurement of Lp-PLA2 mass in human plasma developed by diaDexus, Inc. is presented. Furthermore, potential clinical applications of Lp-PLA2 mass measurements are proposed.
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PMID:Lp-PLA2: an emerging biomarker of coronary heart disease. 1196 98

The deposition of cholesterol ester within foam cells of the artery wall is fundamental to the pathogenesis of atherosclerosis. Modifications of low density lipoprotein (LDL), such as oxidation, are prerequisite events for the formation of foam cells. We demonstrate here that group X secretory phospholipase A2 (sPLA2-X) may be involved in this process. sPLA2-X was found to induce potent hydrolysis of phosphatidylcholine in LDL leading to the production of large amounts of unsaturated fatty acids and lysophosphatidylcholine (lyso-PC), which contrasted with little, if any, lipolytic modification of LDL by the classic types of group IB and IIA secretory PLA2s. Treatment with sPLA2-X caused an increase in the negative charge of LDL with little modification of apolipoprotein B (apoB) in contrast to the excessive aggregation and fragmentation of apoB in oxidized LDL. The sPLA2-X-modified LDL was efficiently incorporated into macrophages to induce the accumulation of cellular cholesterol ester and the formation of non-membrane-bound lipid droplets in the cytoplasm, whereas the extensive accumulation of multilayered structures was found in the cytoplasm in oxidized LDL-treated macrophages. Immunohistochemical analysis revealed marked expression of sPLA2-X in foam cell lesions in the arterial intima of high fat-fed apolipoprotein E-deficient mice. These findings suggest that modification of LDL by sPLA2-X in the arterial vessels is one of the mechanisms responsible for the generation of atherogenic lipoprotein particles as well as the production of various lipid mediators, including unsaturated fatty acids and lyso-PC.
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PMID:Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation. 1202 Dec 77

Secretory non-pancreatic phospholipase A(2) (sPLA(2)) has been implicated in inflammation and has been found in human atherosclerotic lesions. To test the effect of sPLA(2) deficiency on atherosclerosis, C57BL/Ks mice (apoE(+/+) and PLA(2)(++) were bred with C57BL/6 apoE knockout mice which are sPLA(2)(--) due to a spontaneous mutation. Sibling pairs of mice (apoE(--)/sPLA(2)(++) and apoE(--)/sPLA(2)(--)) on high fat Western diets were dissected at 22 weeks. In vitro enzyme assays confirmed higher serum sPLA(2) activity in the sPLA(2)(++) compared to sPLA(2)(--) for both sexes, while sPLA(2)(--) males had slightly higher serum cholesterol and phospholipids. Analysis of lipoprotein profiles by FPLC showed no effect of sPLA(2) genotype on any measured parameters. Atherosclerosis was quantitated by assaying cholesterol in aortic extracts. Male sPLA(2) trended slightly higher than sPLA(2)(++) with no statistical significance. Female sPLA(2)(++) and sPLA(2)(--) mice showed no significant differences in any of the measured parameters. These results suggest that the endogenous mouse sPLA(2) gene does not significantly affect HDL or atherosclerosis in mice.
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PMID:Deficiency in sPLA(2) does not affect HDL levels or atherosclerosis in mice. 1205 45

Secretory phospholipase A(2) group IIA(sPLA(2) IIA) can be produced and secreted by various cell types either constitutionally or as an acute-phase reactant upon stimulation by proinflammatory cytokines. The enzyme prefers phosphatidylethanolamine and phosphatidylserine as substrates. One important biological function may be the hydrolytic destruction of bacterial membranes. It has been demonstrated, however, that sPLA(2) can also hydrolyse the phospholipid monolayers of high density lipoprotein (HDL) and low density lipoprotein (LDL) in vitro. Secretory phospholipase A(2)-modified LDL show increased affinity to glycosaminoglycans and proteoglycans, a tendency to aggregate, and an enhanced ability to deliver cholesterol to cells. Incubation of cultured macrophages with PLA(2)-treated LDL and HDL is associated with increased intracellular lipid accumulation, resulting in the formation of foam cells. Elevated sPLA(2)(IIA) activity in blood serum leads to an increased clearance of serum cholesterol. Secretory phospholipase A(2)(IIA) can also be detected in the intima, adventitia and media of the atherosclerotic wall not only in developed lesions but also in very early stages of atherosclerosis. The presence of DNA of Chlamydia pneumoniae, herpes simplex virus, and cytomegalovirus was found to be associated with sPLA(2)(IIA) expression and other signs of local inflammation. Thus, sPLA(2)(IIA) appears to be one important link between the lipid and the inflammation hypothesis of atherosclerosis.
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PMID:Biological effects of secretory phospholipase A(2) group IIA on lipoproteins and in atherogenesis. 1205 81

Secretory phospholipase A(2) (sPLA(2)) has been reported to be involved in cell proliferation in general and in endothelial cell migration, processes required for capillary formation. Subsequently, we examined the potential control of angiogenesis by sPLA(2) inhibition, using a cell-impermeable sPLA(2) inhibitor composed of N-derivatized phosphatidyl-ethanolamine linked to hyaluronic acid. This inhibitor effectively inhibits the proliferation and migration of human bone marrow endothelial cells in a dose-dependent manner, and suppresses capillary formation induced by growth factors involved in vascularization of tumors and of atherosclerotic plaques. It is proposed that sPLA(2) inhibition introduces a novel approach in the control of cancer development and atherosclerosis.
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PMID:Control of capillary formation by membrane-anchored extracellular inhibitor of phospholipase A(2). 1209 29

The abundant secretion of type IIA secreted phospholipase A(2) (sPLA(2)) is a major feature of the inflammatory process of atherosclerosis. sPLA(2) is crucial for the development of inflammation, as it catalyses the production of lipid mediators and induces the proliferation of smooth muscle cells. We have analysed the activation of sPLA(2) transcription by cAMP and interleukin-1beta (IL-1beta), and shown that the 500 bp region upstream of the transcription start site of the rat sPLA(2) gene is implicated in activation by synergistically acting cAMP and IL-1beta. We transiently transfected and stimulated rat smooth muscle cells in primary culture and measured the promoter activities of serial and site-directed deletion mutants of sPLA(2)-luciferase constructs. A distal region, between -488 and -157 bp, bearing a CAAT/enhancer binding protein (C/EBP)-responsive element (-242 to -223) was sufficient for cAMP/protein kinase A-mediated sPLA(2) promoter activation. We find evidence for the first time that activation of the sPLA(2) promoter by IL-1beta requires activation of an Ets-responsive element in the -184 to -180 region of the distal promoter via the Ras pathway and a nuclear factor-kappaB site at positions -141 to -131 of the proximal promoter. We also used electrophoretic mobility shift assays to identify five binding sites for the Sp1 factor; a specific inhibitor of Sp1, mithramycin A, showed that this factor is crucial for the basal activity of the sPLA(2) promoter.
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PMID:Transcriptional regulation of the rat type IIA phospholipase A2 gene by cAMP and interleukin-1beta in vascular smooth muscle cells: interplay of the CCAAT/enhancer binding protein (C/EBP), nuclear factor-kappaB and Ets transcription factors. 1218 23


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