The Expression and Localization of Plasma Platelet-activating Factor Acetylhydrolase in Endotoxemic Rats

Howard, Katherine M.; Olson, Merle S.

doi:10.1074/jbc.m001462200

Cited by 33 publications

(30 citation statements)

References 26 publications

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“…Thus, the release of Lp-PLA 2 occurs independently of lipoprotein secretion; the enzyme subsequently associates with these particles ( 1 ). Lp-PLA 2 is actively produced and secreted by monocyte-derived macrophages in response to infl ammatory cytokines and microbial lipopolysaccharides (43)(44)(45)(46)(47). Hypercholesterolemic patients exhibit a low grade infl ammation, as is indicated by the higher hsCRP levels compared with controls, a fi nding that is in accordance with our previously published results ( 48 ).…”

Section: Discussionsupporting

confidence: 90%

The elevation of apoB in hypercholesterolemic patients is primarily attributed to the relative increase of apoB/Lp-PLA2

Tellis

Moutzouri

Elisaf

et al. 2013

Journal of Lipid Research

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Section: Discussionsupporting

confidence: 90%

The elevation of apoB in hypercholesterolemic patients is primarily attributed to the relative increase of apoB/Lp-PLA2

Tellis

Moutzouri

Elisaf

et al. 2013

Journal of Lipid Research

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“…Indeed, an increase in plasma Lp-PLA 2 activity in patients with sepsis ( 54,55 ) or AIDS ( 21 ) has been reported. On the other hand, some studies showed that total plasma Lp-PLA 2 activity is decreased in sepsis ( 22,(56)(57)(58). In our study, total plasma Lp-PLA 2 and HDL-Lp-PLA 2 activities as well as the ratio of total plasma Lp-PLA 2 /ApoB did not signifi cantly differ between and PON1 (paraoxonase) activities was noticed ( Table 2 ).…”

Section: Pon1 (Paraoxonase) and Pon1 (Arylesterase) Activitiessupporting

confidence: 42%

Persistence of an atherogenic lipid profile after treatment of acute infection with brucella

Apostolou

Gazi

Kostoula

et al. 2009

Journal of Lipid Research

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This article is available online at http://www.jlr.org herpes simplex virus, helicobacter pylori, as well as periodontitis have been studied ( 2-4 ). On the contrary, other studies have disputed the causal role of infectious agents in atherogenesis ( 5-7 ).Current evidence suggests that atherosclerosis develops as a response to infl ammatory stimulus. Therefore, common or uncommon infections could represent a risk factor. Mechanisms that may be implicated in the atherogenesis caused by infectious agents include local increase of proinfl ammatory cells, local effusion of endotoxins, autoimmune reaction, systemic cytokine release, and changes in lipid metabolism ( 8 ).Infection and infl ammation cause similar cytokineinduced changes in lipid and lipoprotein metabolism ( 9 ). These include reductions in serum levels of total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), apolipoproteins (Apo) AI and B, and lipoprotein (a) [Lp(a)] and increases in triglyceride (TG) and ApoE concentrations ( 9-14 ).Current evidence suggests that the host response to infection and infl ammation increases oxidized lipids in serum and induces LDL oxidation in vivo. Oxidative modifi cation of LDL is an important event in the development of atherosclerosis ( 15 ). In addition, the cholesterol ester transfer protein (CETP) plays a central role in HDL metabolism and the regulation of HDL-C levels in serum. High levels of CETP activity lead to a reduction in HDL-C levels and an atherogenic lipoprotein profi le ( 16 ).Platelet-activating factor (PAF) is a potent pro-infl ammatory phospholipid produced by activated platelets, -C), ApoB, ApoAI, and ApoCIII and higher LDL-C/HDL-C and ApoB/ApoAI ratios; 2 ) higher levels of IL-1b, IL-6, and TNFa; 3 ) similar ApoCII and oxLDL levels and Lp-PLA 2 activity, lower PON1, and higher CETP activity; and 4 ) higher small dense LDL-C concentration. Four months later, increases in TC, HDL-C, LDL-C, ApoB, ApoAI, and ApoCIII levels, ApoB/ApoAI ratio, and PON1 activity were noticed compared with baseline, whereas CETP activity decreased. LDL-C/HDL-C ratio, ApoCII, and oxLDL levels, Lp-PLA 2 activity, and small dense LDL-C concentration were not altered. Brucella infection is associated with an atherogenic lipid profi le that is not fully restored 4 months following treatment. There is increasing evidence that a link exists between infection/infl ammation and atherosclerosis ( 1 ). Infections with chlamydia pneumoniae, cytomegalovirus,

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“…In another study involving human non-adherent monocyte-macrophage cells (Mono-Mac 6; MM6) it was found that both PAF and LPS were able to up-regulate the expression of PAF AH in a dose dependent manner. The specific PAFR inhibitor WEB2170 was able to completely block the PAF stimulated up-regulation of PAF AH and also inhibited the PAF AH production in the tested cell line but also in rats (Howard & Olson, 2000), after LPS stimulation. The p38 MAPK inhibitor, SB203580 inhibited by 60% the up-regulation of PAF AH after LPS stimulation while PAF stimulation was not affected.…”

Section: Paf Levels and Paf Ah Lp-pla2 Expressionmentioning

confidence: 84%

Computational Investigation of Darapladib and Rilapladib Binding to Platelet Activating Factor Receptor. A Possible Mechanism of Their Involvement in Atherosclerosis

Papakyriakou

Stamatakis²,

Demopoulos³

2014

IJC

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Platelet Activating Factor (PAF), the most potent inflammatory mediator, is involved in a wide range of pathophysiological actions. PAF signal transduction is mediated through PAF receptors (PAFR) that are coupled with several isoforms of G-proteins. PAF hydrolysis is mediated through specific enzymes clustered as PAF acetylhydrolases (PAF-AH). The plasma isoform is known as lipoprotein-associated PLA2 (Lp-PLA2), and is considered a marker, or a mediator in the mechanism of atherosclerosis. Darapladib and rilapladib are selective Lp-PLA2 inhibitors. They are, thus, proposed as a novel therapeutic approach for cardiovascular disease (CVD). The data derived from the computational methods used in this paper suggest that darapladib and rilapladib are potential PAFR antagonists, predicted to bind inside the PAF-binding site with a comparable binding affinity to the endogenous agonist (ΔG = -11.1 Kcal mol -1 ). Darapladib (ΔG = -10.6 Kcal mol -1 ) exhibited a higher affinity than rilapladib (ΔG = -8.2 Kcal mol -1 ). The fact that darapladib down-regulates PAFR expression, while PAFR inhibitors down-regulate the expression of CD36, could be the biochemical explanation in the observed necrotic core reduction, both in animals and humans. The reported results in conjunction with bibliographical data lead to the hypothesis that the involvement of darapladib and rilapladib in atherosclerosis could be through direct inhibition of PAF activity as well as modification of PAF metabolism.

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The Expression and Localization of Plasma Platelet-activating Factor Acetylhydrolase in Endotoxemic Rats

Cited by 33 publications

References 26 publications

The elevation of apoB in hypercholesterolemic patients is primarily attributed to the relative increase of apoB/Lp-PLA2

The elevation of apoB in hypercholesterolemic patients is primarily attributed to the relative increase of apoB/Lp-PLA2

Persistence of an atherogenic lipid profile after treatment of acute infection with brucella

Computational Investigation of Darapladib and Rilapladib Binding to Platelet Activating Factor Receptor. A Possible Mechanism of Their Involvement in Atherosclerosis

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