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)

Ethanol (88-880 mmol/l) inhibited the formation of proaggregatory, vasoconstricting thromboxane A2 (TxA2) during whole blood clotting and during thrombin-induced aggregation of platelet rich plasma. This inhibition was counteracted by the addition of exogenous arachidonic acid, which suggested that ethanol suppressed the liberation of arachidonic acid, evidently by inhibiting phospholipase A2. Ethanol had no effect on the formation of prostacyclin (PGI2, epoprostenol), the endogenous antagonist of TxA2, by human lung. Thus our results suggest that ethanol may shift the balance between TxA2 and PGI2 to the dominance of antiaggregatory, vasodilating PGI2 by suppressing the release of arachidonic acid in platelets. This finding might partly explain why ethanol protects against atherosclerosis and also the increased risk of subarachnoidal haemorrhage after heavy ethanol intake.
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PMID:Ethanol inhibits platelet thromboxane A2 production but has no effect on lung prostacyclin synthesis in humans. 636 50

The ability of platelets to synthetise thromboxane B2 and hydroxylated fatty acids from arachidonic acid was studied simultaneously with arachidonic acid-induced aggregation in 42 patients suffering from severe cerebral atherosclerosis and also in 34 healthy controls. Additionally, phospholipase-A2-induced aggregation was performed as a probe for arachidonic acid located at the platelet surface. All the assays were performed with washed platelets, eliminating a possible influence of plasma. Platelets from patients were found responsive to significantly lower concentrations of arachidonic acid whereas thromboxane and hydroxylated fatty acid biosynthesis did not differ from controls. In the experimental conditions used, 75% of the control platelets underwent aggregation with phospholipase A2 plus sphingomyelinase C, in comparison to only 50% for the patients, indicating the necessity for further analysis of the platelet membrane lipids in atherosclerosis.
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PMID:Platelet arachidonic acid metabolism in severe cerebrovascular disease. 681 8

Because lecithin-cholesterol acyltransferase (LCAT) has been shown to carry out acylation of lysolecithin as well as hydrolysis of lecithin in addition to an esterification of cholesterol, the cofactor requirements of the three reactions catalyzed by the enzyme were studied. The purified enzyme required apolipoprotein A-I (apo A-I) for both the phospholipase A2 activity (release of free fatty acids from lecithin) and cholesterol esterification, whereas, low density lipoprotein (LDL) was required for the acylation of lysolecithin. Apo A-I and lecithin liposomes could not substitute for LDL for the activation of lysolecithin acyltransferase activity. Removal of apo A-I from the LDL preparation by affinity chromatography did not affect the activation of lysolecithin acylation, indicating that the contaminating apo A-I is not responsible for the activation. LDL facilitates cholesterol esterification in presence of labelled lecithin liposomes by providing the unesterified cholesterol. Removal of contaminating apo A-I, however, abolishes this LCAT activity which could be restored by addition of pure apo A-I. Lysolecithin inhibits both phospholipase A2 and LCAT activities, but LDL appeared to attenuate the effects of lysolecithin, in addition to stimulating the acylation of lysolecithin. These results show that apo A-I is not obligatory for all the reactions carried out by the enzyme, and that LDL plays an important role in the regulation of the hydrolysis and acylation reaction carried out by the enzyme.
Atherosclerosis 1982 Nov
PMID:Studies on the cofactor requirement for the acylation and hydrolysis reactions catalyzed by purified lecithin-cholesterol acyltransferase. Effect of low density lipoproteins and apolipoprotein A-i. 715 94

Atherogenesis is characterized by a proliferation of arterial smooth muscle cells that may be of transformed nature. Platelets are implicated in the progression of atherosclerotic lesions through thrombotic complications. The present study was designed to investigate whether transformed arterial smooth muscle cells (SMC) could specifically aggregate platelets. We used rat transformed arterial SMC lines, V6- and V8-lines, that we had previously established. Experiments were performed with an in vitro homologous rat system. Suspensions of SMC were added without any other aggregating agent to rat heparinized platelet-rich plasma (PRP) in a coagulo-aggregometer. The effect of transformed V6-line and V8-line SMC was compared to that of their normal parental counterparts, V6- and V8-parent cells. Suspensions of transformed SMC induced, in a dose-dependent manner, an immediate and reversible ADP-like platelet aggregation. The amplitude of platelet aggregation was much higher with addition of transformed cells than of the corresponding control SMC (7.39 +/- 0.75 cm vs. 0.85 +/- 0.62 cm with 2 x 10(6) SMC, V6-line vs. V6-parent cells, respectively). ADP-like aggregation did not significantly differ between the two transformed V6- and V8-lines. ADP-like platelet aggregation was also obtained with supernatants of transformed SMC suspensions, the amplitude being higher with supernatants than with cell suspensions (21.0 +/- 3.64 cm vs. 6.8 +/- 1.22 cm with 1.0 x 10(6) V8-line cells, supernatant vs. cell suspension, respectively). The transformed SMC-induced aggregation of platelets was inhibited by apyrase (125 microM) and iodoacetate (25 mM) and thus was ascribable to ADP released by the SMC. In addition, all suspensions of SMC, normal or transformed, but not their supernatants, induced plasma clotting after variable coagulation times. Coagulation was inhibited by hirudin (25 to 100 U/ml) and phospholipase A2 (10 U/ml) indicating thrombin generation through activity of the SMC membrane tissue factor. The present results show that transformed arterial smooth muscle cells may directly aggregate platelets via a release of ADP and this could be of pathophysiological relevance for thrombosis associated with atherosclerosis.
Atherosclerosis 1994 Oct
PMID:Transformed rat arterial smooth muscle cells induce platelet aggregation. 784 66

Platelet-activating factor (PAF) has been implicated as a mediator of inflammation and atherosclerosis. A specific degradative enzyme found in plasma, PAF acetylhydrolase, plays important roles in various pathophysiological events induced by PAF. Human macrophages and Hep G2 cells secrete PAF acetylhydrolase with characteristics identical to the plasma activity. Other investigators reported that apolipoprotein B may possess phospholipase A2 activity, which suggested that apolipoprotein B might be a zymogen for PAF acetylhydrolase. However, while macrophages express PAF acetylhydrolase activity, we did not detect cDNAs for apolipoprotein B in a cDNA library from these cells, indicating that macrophages do not express this protein. In contrast, Hep G2 cells had high levels of cDNA for apolipoprotein B, as expected. We next injected Xenopus laevis oocytes with poly(A)+ RNA extracted from cultured human macrophages and Hep G2 cells. Twenty-five to 50% of Xenopus oocytes injected with poly(A)+ RNA from macrophages or Hep G2 cells secreted a PAF acetylhydrolase activity (1.0-7.8 nmol/ml per h) that also utilized a synthetic oxidized phospholipid as substrate. The activity secreted by poly(A)+ RNA-injected oocytes associated with lipoproteins and transferred between the particles in a pH-dependent manner, much like the plasma activity. These experiments establish that the properties of the enzyme released from poly(A)+ RNA-injected oocytes are identical to those of the plasma form of PAF acetylhydrolase and that the activity detected is not the expression of a domain in apolipoprotein B.
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PMID:Characterization of the platelet-activating factor acetylhydrolase from human plasma by heterologous expression in Xenopus laevis oocytes. 793 48

Lipids are components of our diet and luminal secretions, with physicochemical characteristics that determine their digestion and absorption in the gastrointestinal tract. Lipids include triglycerides, phospholipids, and cholesterol. Dietary lipids contain approximately 97% triglycerides, with small amounts of phospholipids and cholesterol. These components are important in cell membrane composition, fluidity, peroxidation, prostaglandin and leukotriene synthesis, and cellular metabolic processes. Lipids are implicated in the mechanisms of brain development, inflammatory processes, atherosclerosis, carcinogenesis, aging, and cell renewal. Duodenal hydrolysis of dietary lipids and biliary phospholipids and cholesterol is carried out by pancreatic lipase, colipase, phospholipase A2, and cholesterol esterase. Bile acid solubilization results in mixed micelles and liposomes, in gel and liquid crystal phases. Lipid digestion products pass across the intestinal unstirred water layer. For long-chain fatty acids and cholesterol, passage across the unstirred water layer is rate limiting, whereas passage of short- and medium-chain fatty acids is limited by the brush-border membrane. Within the unstirred water layer, an acidic microclimate aids micellar dissociation so that protonated, and to a lesser extent, nonprotonated monomers then pass across the intestinal brush-border membrane. Absorptive mechanisms have been studied extensively in relation to lipid composition, fatty acid chain length, degree of unsaturation, essential fatty acid content, phospholipid components, and cholesterol. Enterocytes may take up lipids from the intestinal lumen or from lipoproteins of the bloodstream, but these pools are likely to be functionally distinct. Recent advances are reviewed, including recent advances in the area of microclimates, compartmentation, lipid binding proteins, intracellular trafficking, intestinal lipoproteins, release of lipids across the basolateral membrane, and dietary effects.
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PMID:Lipid absorption: passing through the unstirred layers, brush-border membrane, and beyond. 830 92

Atherosclerotic plaques exhibit a series of features that are similar to those of chronic inflammation. Based on the fact that during inflammation several cell types synthesize and secrete a group II phospholipase A2 (PLA2), an immunohistochemical study was undertaken to explore whether this enzyme can be identified in human atherosclerotic lesions. Tissue specimens obtained from 13 patients who had undergone arteriectomy and three specimens with advanced atherosclerotic plaques obtained at autopsy were analyzed and compared to arteries free of atherosclerosis. The results showed that in all areas with atherosclerotic lesions, a staining with monoclonal antibodies raised against group II PLA2 was evident. In normal arteries without thickened intima, this immunostaining was completely negative. With the use of specific monoclonal antibodies against macrophages (anti-KP-1) and smooth muscle cells (anti-alpha-actin), PLA2-positive cells were identified as foam cells mainly derived from macrophages. In addition to these cells, other regions of the thickened intima gave a partially positive reaction with anti-PLA2 antibodies, but could not be stained with either anti-KP-1 or anti-alpha-actin. Some of these regions were localized on edges of calcification and cell necrosis. Other PLA2-positive regions seem to be associated with extracellular matrix structures. In summary, the findings of this study may be regarded as further evidence to support the link between atherosclerosis and chronic inflammatory processes. In view of the fact that the in vitro modification of lipoproteins by PLA2-treatment induces lipid deposition in macrophages, the results of this study suggest that group II PLA2 may actively be involved in the formation of foam cells in vivo.
Atherosclerosis 1995 Dec
PMID:Secretory group II phospholipase A2 in human atherosclerotic plaques. 912 19

The immunoreactivity of high density lipoprotein (HDL) modified by treatment with porcine pancreatic phospholipase A2 (PLA2) was studied in a competitive radioimmunoassay using 6 different monoclonal apolipoprotein (apo) A-I antibodies. The competition tests have shown that after PLA2 treatment the immunoreactivity of selected epitopes of apo A-I changed in different ways. While the binding behavior of two epitopes remained unchanged, three epitopes exhibited decreased immunoreactivities after phospholipids hydrolysis. In contrast to the latter epitopes, the immunoreactivity of an epitope located on the cyanogen bromide fragment 4 of apo A-I increased with the degree of lipolysis. A loss of apo A-I from HDL as a consequence of PLA2-treatment did not occur as shown by the determination of the apo A-I concentration in HDL before and after treatment with PLA2. Using overlapped synthetic decapeptides it could be shown that the epitope increasingly exposed on the particle surface of PLA2-modified HDL consists of the amino acid residues 162-173 and 212-229. These residues are characterized by high hydrophobic indices as determined by hydropathy analysis. Furthermore, these regions belong partially to the proposed receptor-binding domain of apo A-I. Thus, an increased exposition of this epitope might result in elevated cellular binding affinities of HDL occurring after modification of lipoproteins by PLA2-treatment.
Atherosclerosis 1995 Oct
PMID:Changes in epitope exposition of apolipoprotein A-I on the surface of high density lipoproteins after phospholipase A2 treatment. 880 61

The oxidative modification of low density lipoprotein (LDL) and the endothelial expression of adhesion molecules are key events in the pathogenesis of atherosclerosis. In this study we evaluated the effect of oxidized LDL on the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on human umbilical vein endothelial cells (HUVECs). The hypothesis that oxidized LDL functions as a prooxidant signal was also evaluated, by studying the effect of different radical-scavenging antioxidants on expression of adhesion molecules. LDL was oxidized by using Cu2+, HUVECs or phospholipase A2 (PLA2)/ soybean lipoxygenase (SLO), the degree of oxidation being measured as thiobarbituric acid-reactive substances (TBARS) and conjugated dienes (CD). Exposure of 200 micrograms/ml of native LDL to 1 microns Cu2+, HUVECs and to PLA2/ SLO resulted in four- to fivefold higher levels of TBARS and CD than in native LDL. Cu(2+)-(1 microM), HUVEC-, and PLA2/SLO-oxidized LDL caused a dose-dependent, significant increase of ICAM-1 and VCAM-1 (p < .01). The expression of E-selectin did not change. LDL oxidized with a 2.5 and 5 microM Cu2+ did not increase ICAM-1 and VCAM-1 significantly. Both the Cu(2+)- and HUVEC-oxidized LDL, subjected to dialysis and ultrafiltration, induced ICAM-1 and VCAM-1 expression. After incubation with the ultrafiltrate, the expression of ICAM-1 and VCAM-1 was not significantly different from that obtained with native LDL. LDL pretreated with different antioxidants (vitamin E and probucol) and subjected to oxidation by Cu2+ and HUVECs induced a significantly lower expression of ICAM-1 and VCAM-1 than nonloaded LDL (p < .01). The pretreatment of HUVECs with vitamin E and probucol significantly reduced the expression of VCAM-1 on HUVECs induced by oxidized LDL (p < .01); the effect on ICAM-1 was much less evident. In conclusion, oxidized LDL can induce the expression of different adhesion molecules on HUVECs; this induction can be prevented by pretreating either the LDL or the cells with radical-scavenging antioxidant.
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PMID:Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells. 895 36

Secretory nonpancreatic type II phospholipase A2 (snpPLA2) hydrolyzes fatty acids at the sn-2 position in phospholipids releasing free fatty acids (FFAs) and lysophospholipids. These products may act as intracellular second messengers or can be further metabolized into proinflammatory lipid mediators. The presence of snpPLA2 in extracellular fluids and serum during inflammation has suggested a role of the enzyme in this process. However, the presence of snpPLA2 in a variety of normal tissues suggests that snpPLA2 may also have physiological functions. Atherosclerosis appears to have an inflammatory component. Here we report on the snpPLA2 localization in normal and atherosclerotic lesions and on the properties of the isolated enzyme. A strong snpPLA2 immunoreactivity was observed in the arterial media that was colocalized with alpha-actin-positive vascular smooth muscle cells (SMCs) in both normal and atherosclerotic vessels. In aortic atherosclerotic lesions, snpPLA2 was observed colocalized with CD68-positive macrophages and HHF-35-positive SMCs and extracellularly in the lipid core. snpPLA2 was isolated from human normal arteries and from aorta with lesions. The enzyme was isolated by acid extraction of normal arterial tissues followed by immunoaffinity chromatography. The purified snpPLA2 had an expected molecular weight of 14 kD by polyacrylamide gel electrophoresis and appeared as a single band in immunoblotting. The enzymatic activity was followed by measuring release of fatty acids from phospholipid liposomes or LDL as substrates. The enzymatic activity was inhibited with two specific inhibitors for human snpPLA2: (1) monoclonal antibody 187 and (2) LY311727, a synthetic selective inhibitor. The mRNA for snpPLA2 was detected with reverse transcriptase polymerase chain reaction. These results indicate that snpPLA2 is present in human arteries and that it is able to hydrolyze phospholipids in LDL. The results support the hypothesis that snpPLA2 can release proinflammatory lipids at places of LDL deposition in the arterial wall.
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PMID:Localization of nonpancreatic secretory phospholipase A2 in normal and atherosclerotic arteries. Activity of the isolated enzyme on low-density lipoproteins. 908 85


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