UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human plasma platelet activating factor acetylhydrolase (PAF-AH) is an enzyme associated mainly with the apolipoprotein B (apoB)-containing lipoproteins and primarily with low-density lipoprotein (LDL). A small proportion of enzyme activity is also associated with high-density lipoprotein (HDL). PAF-AH activity is essential for the metabolism of PAF and oxidized phospholipids, i.e. bioactive lipids that are involved in the pathophysiology of atherosclerosis. Thus, PAF-AH may play a significant role in atherogenesis. Accumulating data indicate that PAF-AH associated with HDL particles plays a predominantly antiatherogenic role. By contrast, the role of LDL-associated PAF-AH remains controversial. Dyslipidemia induces a significant increase in total plasma PAF-AH activity and alters the enzyme distribution between proatherogenic apoB- and antiatherogenic apo AI-containing lipoproteins by increasing the PAF-AH activity associated with apoB-containing lipoproteins. The decreased rate of LDL removal from the circulation and the abnormal catabolism of triglyceride-rich lipoproteins play important roles in these abnormalities. Atorvastatin or fenofibrate therapy can restore, at least partially, the dyslipidemia-induced alterations in plasma PAF-AH by increasing the ratio of HDL-PAF-AH to plasma PAF-AH (or to LDL-cholesterol) levels, which may represent an important antiatherogenic effect of these hypolipidemic drugs.
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PMID:Effect of hypolipidemic drugs on lipoprotein-associated platelet activating factor acetylhydrolase. Implication for atherosclerosis. 1460 31

Animal models provide vital tools to explicate the pathogenesis of atherosclerosis. Accordingly, we established two atherosclerosis-prone mice models: (i) mice lacking the LDL (low-density lipoprotein) receptor (LDLR) and the ability to edit apo (apolipoprotein) B mRNA (Apobec1; designated LDb : LDLR-/- Apobec1-/-), and (ii) mice with the LDb background, who also overexpressed human apoB100 (designated LTp : LDLR-/- Apobec1-/- ERhB+/+). Both LDb and LTp mice had markedly elevated levels of LDL and increased levels of NEFAs (non-esterified fatty acids) compared with C57BL/6 wild-type mice. However, fasting glucose and insulin levels in both animals were not different than those in C57BL/6 wild-type mice. It has been suggested that PAF-AH (platelet-activating factor acetylhydrolase) increases susceptibility to vascular disease. Both LDb and LTp mice had significantly higher PAF-AH mRNA levels compared with C57BL/6 wild-type mice. PAF-AH gene expression was also significantly influenced by age and sex. Interestingly, PAF-AH mRNA levels were significantly higher in both LTp male and female mice than in the LDb mice. This increased PAF-AH gene expression was associated with elevated plasma PAF-AH enzyme activities ( LTp > LDb > C57BL/6 ). Moreover, a greater proportion of PAF-AH activity was associated with the apoB-containing lipoproteins: 29% in LTp and 13% in LDb mice compared with C57BL/6 wild-type animals (6.7%). This may explain why LTp mice developed more atherosclerotic lesions than LDb mice by 8 months of age. In summary, increased plasma NEFAs, PAF-AH mRNA and enzyme activities are associated with accelerated atherogenesis in these animal models.
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PMID:Increased plasma non-esterified fatty acids and platelet-activating factor acetylhydrolase are associated with susceptibility to atherosclerosis in mice. 1471 54

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

We have previously shown that intravenous apolipoprotein (apo) A-I/phosphatidylcholine (apo A-I/PC) discs increase plasma high-density lipoprotein (HDL) concentration in humans. We have now studied the associated changes in two enzymes, paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH) that are carried in whole or in part by HDLs, and are thought to influence atherogenesis by hydrolyzing oxidized phospholipids in lipoproteins. Apo A-I/PC discs (40 mg/kg over 4 h) were infused into eight healthy males. Although plasma apo A-I and HDL cholesterol increased on average by 178 and 158%, respectively, plasma total PON and total PAF-AH concentrations did not rise. By the end of the infusion, HDL-associated PAF-AH had increased by 0.56 +/- 0.14 microg/mL (mean +/- S.D., P < 0.01), and nonHDL-associated PAF-AH had decreased by 0.84 +/- 0.11 microg/mL (P < 0.05). These changes were accompanied by an increase in the HDL-associated PAF-AH/apo A-I ratio from 0.19 to 0.35 (P < 0.05), and by a decrease in the nonHDL-associated PAF-AH/apo B ratio from 2.1 to 1.4 (P < 0.05). No changes in PON or PAF-AH concentrations were detected in prenodal lymph (tissue fluid), collected continuously from the leg. Our results show that the total concentrations of PON and PAF-AH in plasma are uninfluenced by plasma HDL concentration. PAF-AH transfers readily between HDLs and LDLs in vivo, and its distribution between them is determined partly by their relative concentrations and partly by HDL composition.
Atherosclerosis 2004 Sep
PMID:Effects of intravenous apolipoprotein A-I/phosphatidylcholine discs on paraoxonase and platelet-activating factor acetylhydrolase in human plasma and tissue fluid. 1530 75

The diabetes mellitus is accompanied in its evolution by ample disturbances of the blood's fluid-coagulating equilibrium, which contribute to the initiation and development of the micro and macro-vascular complications. The early and accelerated atherosclerosis in diabetes mellitus obliged the medical world to the necessity to solve the pathogenic implied mechanisms: knowing them allowed us to apply a therapy that can prevent or improve the associated vascular pathology. The intense research made in the last decades mentioned that, in diabetes mellitus, all the stages of the hemostasis are affected, noticing the diminution of the fibrinolysis. The growth of the production of pro-aggregating factors unleashed from the platelets or other cells--TXA2. PAF, and the lowering of the synthesis of the protector endothelial factors--PGI2, NO--are followed by the intensifying adhesion and aggregation growth of the platelets at the injured endothelium, with the worsening of the atherosclerosis injuries. Furthermore, the activated platelets are keeping and are augmenting other steps of the hemostasis--first of all the coagulation, in this way contributing to the stage of hypercoagulability in diabetes mellitus. The deficit of plasminogen activators and the growth of the synthesis of fibrinolysis inhibitors also keep the stage of hypercoagulability, underlined by the growth of plasmatic concentration of the fibrinogen, especially PAI-1. There still are controversies concerning the stage of hypercoagulability whether it is primary in diabetes or it is an answer-reaction to the endothelial damages and the high level of glycaemia. The role of the coagulation-fibrinolyses-thrombocytus-prostaglandins-CFTP in the initiating and development of the micro and macro-vascular complications, as well as in the acceleration of the atheriosclerosis process in diabetes mellitus, is nowadays certitude. More difficult is the attempt to identify the pathogenic mechanisms in which the CFTP sector interferes: the research in this domain still begins under the sign of incertitude.
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PMID:Disturbances of the coagulating equilibrium of blood in diabetes mellitus. 1553 3

Serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated esterase/lactonase implicated to play a role in protection against atherosclerosis. However, the exact mechanism(s) and substrates for PON1 are still uncertain. In this article, we review some of the evidence for PON1's antioxidant activity, as well as our efforts to identify the actual substrates and products for this activity. We originally reported that PON1 had phospholipase activity toward oxidized phosphatidylcholine (J. Biol. Chem. 276:24473-24481; 2001). Subsequently, Marathe et al. (J. Biol. Chem. 278:3937-3947; 2003) reported that this activity was due to a contaminating lipase. However, that article did not replicate the conditions used in our previous study. To address this controversy, we purified serum PON1 by a modified method that separates the paraoxonase activity from an activity detectable as platelet-activating factor acetyl hydrolase (PAF-AH) (Teiber et al., J. Lipid. Res. 2004; Epub ahead of print, PMID 15342686) and reexamined the oxidation of phosphatidylcholine by peroxynitrite using 3-morpholinosydnonimine as a peroxynitrite generator and apolipoprotein AI-phosphatidylcholine- PON1 complexes. The phosphatidylcholines were studied by electrospray ionization tandem mass spectrometry. PON1 preparations free of PAF-AH activity showed no phospholipase activity when reconstituted into apolipoprotein AI-phosphatidylcholine complexes. We conclude that PON1 does not affect the accumulation of phosphatidylcholine oxidation products. Further, we have no evidence that PON1 has an intrinsic phospholipase A2 activity toward oxidized phospholipids.
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PMID:Paraoxonase-1 does not reduce or modify oxidation of phospholipids by peroxynitrite. 1560

Carotid intima media thickness (IMT), represents an important clinical indicator of early atherosclerosis. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme primarily associated with low-density lipoprotein (LDL) while a small proportion of enzymatic activity is also associated with high-density lipoprotein (HDL). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. The authors investigated the possible relationship between carotid IMT and the plasma levels of PAF-AH mass and activity as well as the PON1 activity in hyperlipidemic patients. One hundred unrelated patients with primary hyperlipidemia and 67 age-and sex-matched normolipidemic apparently healthy volunteers participated in the study. The PAF-AH activity in total plasma and in HDL-rich plasma (HDL-PAF-AH activity), the plasma PAF-AH mass, and the serum PON1 activities toward paraoxon and phenyl acetate were determined. The plasma PAF-AH mass and activity were higher in hyperlipidemic patients compared to controls, whereas the HDL-PAF-AH activity, as well as the serum PON1 activities were not significantly different between the studied groups. When hyperlipidemic patients were divided into 2 subgroups according to their IMT values (IMT <0.7 mm and IMT > or =0.7 mm) patients with IMT > or =0.7 mm had significantly higher age, and serum triglyceride concentrations, whereas no difference was found in the plasma PAF-AH mass and activity as well as in the HDL-PAF-AH activity between the 2 studied subgroups. The same phenomenon was observed for serum PON1 activities. In a multivariate analysis, only the age was significantly correlated with IMT values (p<0.05). Neither the total plasma PAF-AH mass and activity nor the HDL-PAF-AH activity are associated with early carotid atherosclerosis.
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PMID:Lack of association between carotid intima-media thickness and PAF-acetylhydrolase mass and activity in patients with primary hyperlipidemia. 1607 29

Inappropriate platelet activation is a feature of acute and chronic diseases such as disseminated intravascular coagulation (DIC) and atherosclerosis. Since proinflammatory microbial-derived agonists can be involved in the pathogenesis of these diseases, we examined the potential role of TLR4 (mediating responses to LPS) and TLR2 (which responds to bacterial lipopeptides) in platelet activation. Our data suggested low-level expression of TLR2 and TLR4 on platelets, determined by flow cytometry, and we also observed expression of TLR4 on a megakaryocytic cell line by both flow cytometry and immunohistochemistry. Stimulation of the platelets with the TLR4 agonist LPS, and the synthetic TLR2 agonist Pam3CSK4, resulted in no platelet aggregation, no increase in CD62P surface expression and no increase in the cytosolic concentration of Ca2+. The TLR agonists were also unable to directly activate platelets primed with epinephrine, or pretreated with a low concentration of ADP or PAF. Pretreatment of platelets with LPS or Pam3CSK4 also failed to modulate the platelet response to submaximal concentrations of the classical platelet agonists ADP and PAF. We conclude that the TLR agonists LPS and Pam3CSK4 have no direct effect on platelet activation and that platelet TLRs may be a remnant from megakaryocytes. TLR2 and TLR4 agonists are thought to have a significant role in diseases such as atherosclerosis and DIC, but our research suggests that this is through a mechanism other than direct platelet activation or by modification of platelet responses to other agonists.
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PMID:Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. 1627 Jun 39

Atherosclerosis as a chronic inflammatory disease resulting from the imbalance of the pro- and anti-inflammatory factors in the vessel wall. PAF and PAF-like oxidized phospholipids generated upon LDL oxidation in the intima of the arteries may interact with infiltrated monocytes/macrophages and lead to the alteration of gene expression patterns accompanied by an impaired production of chemokines, interleukins and proteolytic and lipolytic enzymes. The aim of this study was to evaluate the binding capacity of the major component of PAF-like oxidized phospholipids, namely the 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) to PAF-receptor (PAF-R) on the surface of human monocytes/macrophages and to further characterize the gene expression induced by such binding. We show that, POVPC binds to cultured human macrophages via PAF-R and transduces the signals leading to the intracellular Ca(2+) fluxes and modifies the transcription levels of numerous pro-inflammatory and pro-atherogenic genes. Although a some similarity of the gene expression patterns was observed when macrophages were activated with POVPC versus PAF, we observed that only POVPC treatment induced a several-fold activation of IL-8 gene. In turn, only PAF activated PAF-R, matrix metalloproteinase-13 and 15-lipoxygenase mRNA accumulation. Thus, we suggest, that POVPC signals in mature macrophages only in part through the PAF-R, a part of its effects may involve other receptors.
Atherosclerosis 2006 Oct
PMID:Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophages. Implications in atherosclerosis. 1638 58

Physical activity is known to play a cardioprotective role. Nevertheless, a paradox seems to arise when considering that aerobic exercise enhances oxidative stress. In previous works, we showed that free radical formation during physical activity was counteracted by an increase in antioxidant defenses. Low density lipoprotein (LDL) oxidation is a crucial step in atherosclerosis, process that can be inhibited by high density lipoprotein (HDL) through its oxidable components or associated enzymes like paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH). In this study, we evaluated copper-induced oxidation in isolated LDL and HDL fractions, and the effect of HDL on LDL oxidation in samples from well trained amateur athletes who were participating in an ultra-distance triathlon (n=18) in comparison with healthy sedentary controls (n=18). PON and PAF-AH activities and PON phenotype were also evaluated. The oxidability of isolated lipoproteins, as well as HDL antioxidant capacity, was similar in both groups of subjects. After classification by paraoxonase phenotype, only sportsmen belonging to the QR phenotype showed higher HDL susceptibility to in vitro oxidation (thiobarbituric reactive substances, TBARS) than controls (p<0.05). HDL oxidability exhibited a positive correlation with its triglyceride content (r=0.58; p<0.01). Similarly, HDL capacity to inhibit LDL oxidation was increased in athletes (p<0.05) which was positively associated with HDL oxidability (HDL-TBARS: r=0.55, p<0.005; HDL-lag time: r=0.45, p<0.01; HDL-D max: r=0.35, p<0.05). In conclusion, regular aerobic exercise was associated to a more efficient antioxidant function played by HDL from PON-QR carriers, which could constitute an adaptive response to the increased oxidative stress.
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PMID:HDL capacity to inhibit LDL oxidation in well-trained triathletes. 1648 45

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