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)

Besides the well established role of low density lipoproteins (LDL), the phospholipid PAF-acether (paf) seems to be involved in atherogenesis. The effect of LDL (10 micrograms/ml for 24 h, n = 3) on paf binding characteristics of monocyte/macrophage-like U 937 cells was investigated using the radioligand [3H]paf, unlabeled paf and the paf receptor antagonist WEB 2086. The specific [3H]paf binding significantly increased at 1.4 nM (P less than 0.02) and 2.8 nM (P less than 0.01) added [3H]paf with an increased number of paf binding sites in the Scatchard plot analysis of the data. Specific paf binding was functionally active since paf mediated a cellular [Ca2+]i rise. The protein kinase C (PKC) activator PMA (1 nM, 37 degrees C) expressed specific [3H]paf binding already after a 15-min incubation period, indicating a PKC activation as the decisive step of paf receptor expression. LDL also stimulated the paf degrading cellular acetylhydrolase significantly by increasing both Km (9.4 +/- 1.9 vs. 2.0 +/- 0.5 microM, P less than 0.02) and vmax (0.5 +/- 0.2 vs. 0.2 +/- 0.0 nmol/min per mg cell protein, P less than 0.02). The data demonstrate that LDL increases the number of paf receptors on monocyte/macrophage-like U 937 cells and interferes with the dynamics and/or synthesis of the cellular acetyl hydrolase. These effects could be of importance in the pathogenesis of atherosclerosis.
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PMID:Long time incubation of monocytic U 937 cells with LDL increases specific paf-acether binding and the cellular acetylhydrolase activity. 180 64

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

Platelet aggregation induced by threshold concentrations of agonists such as collagen, PAF or epinephrine was inhibited in vitro by 100 microM aspirin but was restored by stimulating platelets with high concentrations of collagen, PAF or by a combination of epinephrine and PAF. Incubating aspirin-treated platelets with 50-100 microM vitamin E or vitamin E acetate inhibited platelet aggregation by high concentrations of collagen and PAF and by the combination of epinephrine and PAF; platelet thromboxane A2 formation was less than 10% in samples incubated with 100 microM aspirin. Apyrase, added to aspirin-treated platelet, did not influence platelet aggregation induced by epinephrine and PAF. The present study suggests that concentrations of vitamin E as low as 50-100 microM inhibit cyclooxygenase-independent platelet aggregation when combined with an inhibitor of the arachidonate pathway.
Atherosclerosis 1990 Jun
PMID:Inhibition of cyclooxygenase-independent platelet aggregation by low vitamin E concentration. 211 84

The effects of nicergoline (Sermion) on platelet aggregation, plasma viscosity and erythrocyte deformability were evaluated in 11 geriatric patients with cerebral infarction, 2 men and 9 women (ages 61-78, mean age 71.6). Nicergoline was given orally at a dose of 5 mg 3 times daily after meals for 8 weeks. Hematological variables were determined twice prior to the administration and at 4 and 8 weeks after the administration. The platelet aggregation in vitro was determined by the turbidimetric method and the level of circulating platelet aggregates was determined according to the method of Wu-Hoak. Erythrocyte deformability was determined according to the method based on the examination of passing erythrocytes through a filter containing pores smaller than the undeformed cells. Collagen-, arachidonic acid- and PAF-induced platelet aggregation was decreased after nicergoline administration. Erythrocyte deformability was increased and plasma viscosity was also decreased after the administration. Thus the improvement of platelet aggregation, plasma viscosity and erythrocyte deformability in cerebral infarction may prevent disturbing blood flow and may contribute to prevention of formation and progression of thrombosis and atherosclerosis in geriatric patients with cerebral infarction.
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PMID:Effect of nicergoline on platelet aggregation, plasma viscosity and erythrocyte deformability in geriatric patients with cerebral infarction. Preliminary report. 212 5

The specific markers of platelet activation, e.g. platelet aggregation induced with ADP, AA and PAF as well as the levels of Beta-TG, TXB2, 6-keto-PGF1 alpha and cyclic AMP in the patients suffering from obliterative arteriosclerosis of the lower limbs were measured. It was found that these patients revealed hyperfunction of blood platelets expressed in increased sensitivity of platelets to ADP and PAF, increased levels of Beta-TG and TXB2 as well as decreased levels of 6-keto-PGF1 alpha and cyclic AMP. Obtained results support the concept that atherosclerosis consists of a wide-spread functional alteration of various types of cells.
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PMID:Blood platelet function in patients with obliterative arteriosclerosis of the lower limbs. 246 57

Platelet-activating factor (PAF-acether), a phospholipid mediator involved in inflammatory reactions, has been reported to induce endovascular surface lesions. We investigated the possible involvement of PAF-acether in the mechanism of arterial cholesterol deposition. Rabbits fed a normal or hypercholesterolic diet were treated orally for 1 month with BN 52021 (20 mg/kg per day), a specific PAF-acether antagonist, and killed at the end of treatment. Cholesterol feeding resulted in a marked (50-fold) increase in plasma cholesterol. However, the drug had no significant effect on the diet-induced hypercholesterolemia. Free and esterified cholesterol were markedly increased (635%) in the aorta of animals receiving the atherogenic diet. This accumulation was reduced by 36% upon simultaneous administration of BN 52021 (P less than 0.02, n = 15). This decrease essentially affected the esterified cholesterol content. Conversely, BN 52021 showed no effect on the cellular cholesterol esterification, since liver acyl-CoA: cholesterol acyltransferase activity remained unchanged. This study indicates that BN 52021 is effective in reducing cholesterol accumulation in rabbit atherosclerotic aorta, without changing the plasma cholesterol levels.
Atherosclerosis 1989 Aug
PMID:Protective effect of BN 52021, a specific antagonist of platelet-activating factor (PAF-acether) against diet-induced cholesteryl ester deposition in rabbit aorta. 278 99

PAF-acether, a naturally occurring phospholipid, is a potent activator of various biological processes, including platelet aggregation. The mechanisms of action of PAF are largely unknown. We have found that the psychotropic triazolobenzodiazepine drugs, alprazolam and triazolam, potently (IC50 less than 1 microM) inhibit PAF-induced shape change, aggregation and secretion of human platelets. These effects are specific for PAF-activation, since the responses of human platelets to other agonists (ADP, thrombin, epinephrine, collagen, arachidonate and the Ca++ ionophore, A23187) are not inhibited by these triazolobenzodiazepines. The action of triazolobenzodiazepines on PAF-induced platelet function has clinical relevance, especially in diseases where enhanced platelet aggregability may lead to thrombosis and atherosclerosis. In addition, the ability of triazolobenzodiazepines to inhibit other PAF-mediated cellular-responses, such as anaphylactic shock or bronchoconstriction, suggests that these drugs may be useful in preventing several known pathophysiological effects of PAF. The specific antagonism of PAF action by psychotropic drugs also suggests that PAF or PAF-like phospholipids may play a role in neuronal function. This possibility was tested by examining the effects of PAF on neural cells of the clonal line NG108-15, grown in culture in a chemically defined, serum-free medium. Low concentrations of PAF (0.5-2.5 microM) induced neurite extension in NG108-15 cells, whereas higher concentrations (greater than 3 microM) were cytotoxic. Using NG108-15 cells preloaded with aequorin, it was found that PAF causes an increase in intracellular ionized calcium concentration, which is dependent on the presence of extracellular calcium. These results suggest that PAF-induced Ca++ uptake may play a role in neuronal development, and that circulating PAF may contribute to the neuronal degeneration caused by the exposure of neural tissues to blood in situations such as spinal cord injury, trauma, or stroke.
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PMID:Interactions of the alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. 289 25

Human endothelial cells in culture produced platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) when stimulated with leukotriene C4 or D4 (LTC4 or LTD4). Other arachidonate metabolites did not induce the synthesis of PAF. Accumulation of PAF was a prolonged response with maximal accumulation after 10-20 min of stimulation. Half of this amount remained after 90 min of stimulation. The PAF synthesized by endothelial cells remained associated with these cells. LTC4 and LTD4 also induced the adherence of human neutrophils (polymorphonuclear leukocytes; PMNs) to the endothelial cell monolayer. Adhesion was an endothelial cell-mediated process because PMNs adhered to monolayers that had been stimulated and washed prior to PMN addition, and neither LTC4 nor LTD4 stimulated PMNs in the absence of endothelial cells. The time course of PMN adhesion paralleled that of PAF accumulation by endothelial cells, and exogenously added PAF induced adherence. PMNs specifically desensitized to PAF showed only 39% of the agonist-stimulated adherence of control PMNs. We conclude that the PAF synthesized and retained by LTC4- or LTD4-stimulated endothelial cells may induce the adherence of previously unstimulated PMNs. This process may be relevant to inflammation, thrombosis, and mechanisms of vascular injury, including atherosclerosis.
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PMID:Leukotrienes C4 and D4 stimulate human endothelial cells to synthesize platelet-activating factor and bind neutrophils. 345 83

The interactions of blood cells (platelets and leukocytes) with the components of the vessel wall (endothelial cells, extracellular subendothelial matrix and smooth muscle cells) play an important role in the initiation of thrombosis and the development of atherosclerosis. These cellular interactions are partially regulated by the formation of pharmacologically active lipids (PAL): prostaglandins, leukotrienes, PAF-acether and related compounds. These biochemical mediators are produced from the phospholipids of the cell membrane in response to external stimulation. The metabolic precursors, such as arachidonic acid, are common. The subsequent enzymatic differentiation leads to the formation of different terminal products according to the cells, thromboxane A2 in the platelets and prostacyclin in the endothelial cells.
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PMID:[Physiology of the interactions of blood and the blood vessel wall. Role of pharmacologically active lipids]. 393 41

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


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