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)

The effect of cigarette smoking on the levels of platelet-activating factor-like lipid(s) (PAF-LL) in plasma lipoproteins was studied. The subjects were 10 healthy male non-smokers (24 +/- 1.4 years old) and 13 healthy male habitual smokers (23 +/- 1.3 years old). Fasting venous blood was obtained and basal levels of PAF-LL in plasma lipoproteins were estimated. The acute effect of cigarette smoking was also studied in smokers. Plasma lipoproteins were separated by ultracentrifugation. Lipids were extracted and separated by thin-layer chromatography. The fraction with the same migration as authentic PAF was recovered and was shown to cause aggregation of human polymorphonuclear neutrophils. This activity was identified as PAF-LL because it was inactivated by phospholipase A2 and was blocked by CV-3988, an antagonist of the PAF receptor. PAF-LL was detected in LDL and HDL, but not in VLDL or in lipoprotein-deficient plasma. The levels of PAF-LL in LDL in non-smokers, and in smokers before and after smoking were 13 +/- 7.5, 16 +/- 14.9 and 190 +/- 179.0 pg/ml, and those in HDL were 12 +/- 5.2, 40 +/- 40.0 and 235 +/- 205.1 pg/ml, respectively. The values in both LDL and HDL in smokers increased significantly after smoking (P less than 0.05). After 30 min, the levels had returned almost to the pre-smoking levels. We conclude that cigarette smoking induces an increase in the levels of PAF or closely related lipid(s) in LDL and HDL, which may be related to smoking-induced atherosclerosis.
Atherosclerosis 1991 Mar
PMID:Effect of cigarette smoking on the levels of platelet-activating factor-like lipid(s) in plasma lipoproteins. 187 24

Oxidative modification of lipoproteins is believed to be important in the genesis of atherosclerosis. We established cultures of smooth muscle cells (SMC) and exposed them to native LDL or oxidized LDL. Oxidized LDL, but not native LDL, was mitogenic as measured by incorporation of [3H]-thymidine into DNA. This effect was concentration dependent, averaged 288% of control, and was blocked by a platelet-activating factor (PAF) receptor antagonist. We hypothesized that phospholipids with PAF-like activity were generated during the oxidation of LDL. To test this hypothesis we extracted phospholipids from copper-oxidized LDL and assayed for PAF-like activity. Phospholipids extracted from oxidized LDL and purified by HPLC induced neutrophil adhesion equivalent to PAF (10 nM) and were mitogenic for smooth muscle cells. These effects were not seen with phospholipids extracted from native LDL and were blocked by two structurally different, competitive antagonists of the PAF receptor. The effects of these lipids were also abolished by pretreating them with PAF acetylhydrolase. Finally, we used Chinese hamster ovary cells that had seen stably transfected with a cDNA for the PAF receptor to confirm that phospholipids from oxidized LDL act via this receptor. We found that PAF (control) and the oxidized phospholipids each induced release of arachidonic acid from the transfected cells, but had no effect on wildtype Chinese hamster ovary cells, which lack the PAF receptor. This effect was also blocked by a PAF receptor antagonist. Thus, phospholipids generated during oxidative modification of LDL may participate in atherosclerosis by stimulating SMC proliferation and leukocyte activation.
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PMID:Oxidatively modified LDL contains phospholipids with platelet-activating factor-like activity and stimulates the growth of smooth muscle cells. 759 19

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator of numerous inflammatory and thrombotic responses. The purpose of this study was to determine if PAF synthesis is elevated in damaged coronary arteries after a sustained period of cyclic flow variation (CFV), a phenomenon caused by alternating periods of thrombosis and reperfusion at sites of endothelial injury. Cyclic flow was established and maintained in the left anterior descending coronary arteries (LADs) of 10 dogs. After 8 hours of CFV, the section of damaged LAD containing the thrombus and control sections of the circumflex artery, carotid artery, and saphenous vein was excised, and the total lipids were extracted. The PAF was then purified by silica column chromatography and high-performance liquid chromatography and assayed by both a rabbit platelet bioassay and a PAF radioimmunoassay. With the platelet bioassay, PAF levels of 8.9 +/- 4.0 (range, 4.8 to 15.5) pg/mg wet wt were found in the damaged LADs from the 10 dogs. This PAF bioactivity was completely inhibited by a PAF receptor antagonist. When the radioimmunoassay was used, slightly higher PAF levels of 16.3 +/- 12.9 (range, 4.5 to 41.8) pg/mg wet wt were observed in the LADs. Overall, these PAF levels were 3- to 64-fold higher than in the control vessels when either assay method was used. Although increases in PAF were observed in the damaged LADs, measurements of PAF in blood samples taken from the LAD and the aorta (control) failed to demonstrate any site-specific increase of PAF in the blood. In related experiments, PAF was also measured in 23 endarterectomy samples taken from the coronary arteries of 16 patients with severe atherosclerosis. The PAF levels in these samples were highly variable (2.9 +/- 2.2 [range, 0.3 to 8.5] pg/mg wet wt) and showed no correlation with tissue mass, suggesting that PAF is affected by factors other than the simple presence of atherosclerotic tissue in the vessel. These findings provide direct evidence that PAF is synthesized locally at the site of endothelial injury during thrombosis and that PAF accumulates in the atherosclerotic plaque of some patients with advanced coronary artery disease.
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PMID:Measurement of platelet-activating factor in a canine model of coronary thrombosis and in endarterectomy samples from patients with advanced coronary artery disease. 778 82

Platelet-activating factor (PAF) is a phospholipid inflammatory mediator which is synthesized by a variety of cells, including monocytes, endothelial cells, mast cells and neutrophils. PAF acts via a recently cloned PAF receptor, present on monocytes and endothelial cells, but not on non-activated lymphocytes. IL-4 is mainly produced by T lymphocytes, and belongs to the Th2 subset of T helper cells. IL-6 is mainly a monocyte/macrophage-derived cytokine with multiple proinflammatory effects. We here report that PAF induces IL-4 production, as determined by ELISPOT. Antibodies to MHC class II inhibited the IL-4 stimulatory effects of PAF. PAF also had the capacity to induce IgA production, as determined by ELISPOT, and IL-6 production in peripheral blood mononuclear cells (PBMC) as determined by ELISA. These PAF-mediated effects were completely inhibited by a specific PAF-receptor antagonist, WEB 2170. Taken together, our data indicate that PAF activates T lymphocytes to IL-4 production by an indirect, monocyte-dependent mechanism dependent on MHC class II. PAF also enhances antibody formation and IL-6 production from PBMC. These findings indicate that PAF activates immune-competent cells, which may be of importance in inflammatory diseases such as asthma, vasculitis and atherosclerosis.
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PMID:Induction of IL-4 by platelet-activating factor. 887 Jul 12

To clarify the molecular mechanism underlying the lysophosphatidylcholine (LPC) signaling, we studied the effect of LPC on the intracellular free calcium concentration ([Ca2+]i) in murine peritoneal macrophages. LPC when added alone induced biphasic elevation of [Ca2+]i, which consisted of a rapid increase followed by sustained elevation. LPC, when added with equimolar cholesterol, induced only the rapid increase in [Ca2+]i, which was blocked by WEB-2086, a selective platelet-activating factor (PAF) receptor antagonist. These results suggest LPC exerts a specific Ca2+ signaling. The sustained elevation reflected the cell lysis. Furthermore, we confirmed its pathway in a more specific manner using cloned PAF receptors expressed in Chinese hamster ovary cells. LPC induced an elevation of [Ca2+]i in a concentration-dependent manner only when the PAF receptor had been expressed, and the elevation of [Ca2+]i was blocked by WEB-2086. Taken together, LPC transduces Ca2+ signaling via the PAF receptor. Activation of the PAF receptor by LPC may indicate its novel important role in the pathogenesis of atherosclerosis.
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PMID:Lysophosphatidylcholine transduces Ca2+ signaling via the platelet-activating factor receptor in macrophages. 903 18

Platelet activating factor (PAF) is a phospholipid with proinflammatory and thrombogenic properties, which has been implicated in inflammatory disorders including vasculitis and asthma. PAF-like compounds are present in oxidized LDL (oxLDL), which has been detected in the atherosclerotic lesion, where it may activate monocytes, macrophages, and T cells. OxLDL may therefore both initiate and perpetuate inflammatory reactions in the artery wall. Herein we demonstrate that PAF has the capacity to induce enhanced interferon gamma (IFN-gamma) secretion in peripheral blood mononuclear leukocytes (PBMCs), as does oxLDL. Both oxLDL- and PAF-induced IFN-gamma secretions were inhibited by a specific PAF-receptor antagonist, WEB 2170. PAF-like lipids in oxLDL could thus be responsible for oxLDL-induced activation of immune-competent cells. The effects of PAF and oxLDL were inhibited by antibodies to major histocompatibility complex class II and thus depend on accessory cells like monocytes. Both PAF and oxLDL induced tumor necrosis factor-alpha (TNF-alpha) synthesis in peripheral blood. PAF-mediated TNF-alpha production was inhibited by WEB 2170, whereas oxLDL-induced TNF-alpha was only partially inhibited. These findings indicate that both PAF and oxLDL have the capacity to induce TNF-alpha, which may increase atherogenesis due to its pleiotropic proinflammatory effects. Our findings suggest that the PAF receptor plays an important role in the inflammatory component of atherosclerosis.
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PMID:Platelet-activating factor and oxidized LDL induce immune activation by a common mechanism. 915 62

Oxidized low-density lipoprotein (oxLDL) consists of both lipid components and apoprotein B100. OxLDL has both proinflammatory and cytotoxic properties. The present study was undertaken to investigate the effects of components in the lipid moiety of oxLDL on immune activation as determined by cytokine and immunoglobulin secretion. LPC induced interferon-gamma (IFN-gamma) secretion in peripheral blood mononuclear leucocytes from healthy blood donors. The effect varied between individuals, and there were both responders and non-responders. Furthermore, LPC induced enhanced antibody production, indicating B cell activation. None of eight oxysterols, arachidonic acid (AA), or 15-lipoxygenase products of AA tested had immune stimulatory properties. We recently demonstrated that PAF and oxLDL induce IFN-gamma secretion by a common mechanism. LPC-induced IFN-gamma secretion was inhibited by a specific PAF receptor antagonist, WEB 2170, indicating that the PAF receptor is involved in LPC-induced immune activation. Both oxLDL- and LPC-induced antibody formation was inhibited by WEB 2170. Furthermore LPC also induced tumour necrosis factor-alpha secretion, and this effect was inhibited by WEB 2170. LPC is produced during lipid oxidation (as in oxLDL), but also by enzymes such as phospholipase A2. The findings indicate that LPC may play an important role in inflammatory reactions, including atherosclerosis.
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PMID:Lysophosphatidylcholine (LPC) induces proinflammatory cytokines by a platelet-activating factor (PAF) receptor-dependent mechanism. 1033 26

Physical forces induce profound changes in cell phenotype, shape and behavior. These changes can occur in vascular structures as a result of pressure overload and their effects can be seen in atherosclerotic vessels in which smooth muscle cells have undergone hyperplastic and hypertrophic changes. At the molecular level, mechanical stimuli are converted into chemical ones and lead to modulation of gene expression and/or the activation of a new repertoire of genes whose encoded proteins help the cells to adapt to their microenvironment. In this study, we have used a two primer-based mRNA differential display technique to identify candidate mechano-responsive genes in pulmonary artery smooth muscle cells. As compared to the original method described by Liang and Pardee, this technique uses two arbitrary primers instead of an anchored oligo(dt) plus an arbitrary primer in the polymerase chain reaction. The chief advantages of these modifications are an increase in the efficiency of the amplification and in the identification of differentially expressed clones. Using this approach, we compared the pattern of expressed genes in cells cultured under static conditions with those in cells that were mechanically stretched (1 Hz) for 24 h in a well-defined in vitro mechanical system. Three candidate genes that showed reproducible differences were chosen for further characterization and cloning. One clone was under expressed in stretched cells and had a DNA sequence with 90% homology to the human fibronectin gene. Two other clones were highly expressed in stretched cells and had a 92% and a 83% sequence homology with human platelet-activating factor (PAF) receptor and rat insulin-like growth factor-I (IGF-I) genes respectively. Northern blot analysis confirmed low levels of fibronectin mRNA transcripts in stretched cells. In contrast, accumulation of PAF receptor mRNA occurred 30 min after mechanical stretch was initiated whereas IGF-I mRNA levels peaked at 8 h. Both mRNA levels were sustained for up to 24 h of mechanical stretching. These results demonstrate the usefulness of the two primer-based mRNA differential display that enabled us to identify and characterize alterations at the level of gene expression among matrix proteins, G-protein coupled receptors and growth factors, each of whose response to mechanical strain is different. A more complete understanding of these responses will provide further insight into the pathologic processes associated with hypertension and atherosclerosis.
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PMID:Identification of stretch-responsive genes in pulmonary artery smooth muscle cells by a two arbitrary primer-based mRNA differential display approach. 1048 28

Lipid peroxidation is involved in the pathogenesis of chronic diseases including atherosclerosis. Oxidized lipoprotein has diverse biological activities and is believed to initiate atheroma formation and maturate fatty plaque. The active components of oxidized lipoproteins still remain to be clarified, but a likely candidate is the phosphatidylcholine (PC) having an sn-2-short-chain acyl group with a methyl, hydroxyl, aldehydic or carboxylic terminal. These unique PCs, formed by oxidative fragmentation of the polyunsaturated acyl group of the parent PC in liposomes, low density lipoproteins and blood plasma, induce platelet aggregation through the activation of the receptor for platelet-activating factor (PAF), due to their resemblance in structure with PAF. We have found that PAF-like lipids regulate DNA synthesis and production of nitric oxide independently of the activation of the PAF receptor in vascular smooth muscle cells. Regulation of vascular cell function through two distinct signaling pathways mediated by PAF-like lipids provides new insight into the mechanism of induction of atherosclerosis.
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PMID:Platelet-activating factor (PAF)-like oxidized phospholipids: relevance to atherosclerosis. 1123 95

Atherosclerosis has an underlying inflammatory component. Oxidation of low-density lipoprotein (LDL) particles to modified forms promotes atherogenesis by supplying cholesterol and through the oxidative generation of agents that activate macrophages, smooth muscle and endothelial cells. A primary target of oxidizing compounds, derived from cigarette smoke, dietary sources, exuberant inflammatory cell responses and normal cellular metabolism among other sources, are the esterified polyunsaturated fatty acids in the phospholipid shell that surrounds the insoluble lipids of the lipoprotein core. One type of phospholipid oxidation product mimics the structure of the potent inflammatory mediator platelet-activating factor (PAF), and these oxidation products activate the PAF receptor found on platelets, monocytes and leukocytes. Production of such PAF mimetics is, in contrast to the physiologic generation of PAF, uncontrolled. PAF mimetics and other phospholipid oxidation products are found in atherosclerotic lesions or even in blood after exposure to cigarette smoke. Here we summarize our data describing the structure, activity and metabolism of the PAF-like lipids found in atherogenic LDL particles.
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PMID:Oxidized LDL contains inflammatory PAF-like phospholipids. 1168 3


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