- Email: [email protected]
Plasma PAF-acetylhydrolase: An unfulfilled promise?
Biochimica et Biophysica Acta 1761 (2006) 1351 – 1358 www.elsevier.com/locate/bbalip
Review
Plasma PAF-acetylhydrolase: An unfulfilled promise? Sonia-Athina Karabina, Ewa Ninio ⁎ INSERM U525, Université Pierre et Marie Curie-Paris6, Faculté de Médecine Pierre et Marie Curie, 91, bd de l’Hôpital 75634 Paris cedex 13, France Received 30 March 2006; received in revised form 4 May 2006; accepted 8 May 2006 Available online 23 May 2006
Abstract Plasma Platelet-activating-Factor (PAF)-acetylhydrolase (PAF-AH also named lipoprotein-PLA2 or PLA2G7 gene) is secreted by macrophages, it degrades PAF and oxidation products of phosphatidylcholine produced upon LDL oxidation and/or oxidative stress, and thus is considered as a potentially anti-inflammatory enzyme. Cloning of PAF-AH has sustained tremendous promises towards the use of PAF-AH recombinant protein in clinical situations. The reason for that stems from the numerous animal models of inflammation, atherosclerosis or sepsis, where raising the levels of circulating PAF-AH either through recombinant protein infusion or through the adenoviral gene transfer showed to be beneficial. Unfortunately, neither in human asthma nor in sepsis the recombinant PAF-AH showed sufficient efficacy. One of the most challenging questions nowadays is as to whether PAF-AH is pro- or anti-atherogenic in humans, as PAF-AH may possess a dual pro- and anti-inflammatory role, depending on the concentration and the availability of potential substrates. It is equally possible that the plasma level of PAF-AH is a diagnostic marker of ongoing atherosclerosis. © 2006 Elsevier B.V. All rights reserved. Keywords: PAF-AH; Lp-PLA2; LDL-PLA2; PLA2; Oxidized phospholipid; Inflammation; Atherogenesis
1. Introduction Over the past years, a substantial amount of research has focused on an unusual secretory Ca2+-independent phospholipase A2 (PLA2) belonging to the group VIIA, the plasma Platelet-activating-Factor (PAF)-acetylhydrolase (PAF-AH also named lipoprotein-PLA2 or PLA2G7 gene) which degrades PAF [1] (Fig. 1A) and the oxidation products of phosphatidylcholine [2,3] (Fig. 1B). Phosphatidylcholine containing arachidonate at the sn-2 position of glycerol is abundant in low density lipoproteins (LDL) and upon oxidation gives raise to numerous oxidized products with short chains at sn-2 position of glycerol. Such truncated oxidized phospholipids were either isolated from oxidized LDL (oxLDL) or
produced upon oxidation of synthetic 1-palmitoyl-2-arachidonylsn-glycero-3-phosphatidylcholine (oxPAPC) and further functionally characterized in cell culture [4]. Some of these molecules express PAF-like activity, as their effects are attenuated by the specific PAF antagonists [5] and they are degraded by plasma PAFAH [6]. The degradation products of oxPAPC and PAF, mediated by PAF-AH, namely the lysophosphatidylcholine (lyso-PC) and lyso-PAF and short chain fatty acids, may possess deleterious properties on the vessel wall [7,8]. Finally, numerous proinflammatory cells produce and secrete PAF. The purpose of the current review is to summarize the latest views on plasma PAF-AH and its implications in inflammation and in atherosclerosis. 2. Cellular sources and association with lipoproteins
Abbreviations: CAD, coronary artery disease; HDL, high density lipoproteins; LDL, low density lipoproteins; LPS, lipopolysaccharide; Lyso-PAF, lyso-Plateletactivating-factor; Lyso-PC, lysophosphatidylcholine; oxLDL, oxidized LDL; oxPAPC, oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphatidylcholine; PC, phosphatidylcholine; PLA2, phospholipase A2; POVPC, 1-pamitoyl-2oxovaleroyl(5 carbons)-sn-glycero-3-phosphocholine; PPARγ, peroxisome proliferator-activated receptor γ; PAF, Platelet-activating-Factor; rPAF-AH, recombinant PAF-AH ⁎ Corresponding author. Tel.: +1 331 40 77 97 68; fax: +1 331 40 77 97 68. E-mail address: [email protected] (E. Ninio). 1388-1981/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2006.05.008
Mature murine macrophages [9], antigen-activated bone-marrow-derived and serosal mast cells [10] and human mature macrophages [11] and activated platelets [12,13] synthesize and excrete active PAF-AH (Fig. 2); a myeloid origin of this enzyme was confirmed later by showing that the recipients of bone marrow transplantation from PAF-AH deficient donors (Val279Phe substitution) became also deficient [14]. In early pregnancy in mice, PAF-AH was found in uterine endometrium and luminal fluids and
1352
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
Fig. 1. Degradation of PAF into lyso-PAF (A) and oxidized PC into lyso-PC (B) by PAF-AH; n = 14 to 16.
had the same biochemical characteristics as the plasma form of the enzyme and its source was plasma [15]. Secretion of PAF-AH was also described from human decidual macrophages suggesting its role in parturition [16]; moreover lipopolysaccharide (LPS) inhibited PAF-AH secretion suggesting that the resulting accumulation of PAF may be involved in preterm labor caused by endotoxin [17]. Secreted PAF-AH is mainly associated with LDL and to lesser extent with high density lipoproteins (HDL) [18]; its association with small dense LDL particles [19,20] and with electronegative LDL subfractions was documented [21]. In plasma rich in lipoprotein (a), PAF-AH has a tendency to bind to this unusual and pro-atherogenic lipoprotein [22,23]. Among plasma lipoproteins only HDL are endowed with antiatherogenic and anti-inflammatory properties. We have shown that the macrophage PAF-AH is highly glycosylated and for this reason it is relatively poorly associated with human HDL [24], as only 20 to 30% of the total plasma activity is recovered in these particles [18,25]. PAF-AH is probably the unique enzyme in HDL endowed with PLA2 activity towards PAF and PAF-like molecules [26]; plasma isolated from subjects bearing a missense mutation (Val279Phe substitution) in exon 9 of PAF-AH, leading to a complete loss of PAF-AH catalytic activity [27], hydrolyzes neither PAF nor its analogues and is no longer protective against oxidation [26]. However, this plasma contains intact activities of both paraoxonase and lecithin-cholesterol acyltransferase that were claimed to hydrolyze PAF in vitro [3,28–30]. Presently it cannot be excluded that upon inflammation other secretory PLA2 could be secreted and transported on HDL [31].
Of interest, the oxidation process severely inhibits PAF-AH [32,33] and permits accumulation of PAF and oxidized truncated phospholipids with PAF activity [34] (Fig. 2). Accumulation of such oxidized phospholipids in some circumstances may inhibit LPS-induced NFκB-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14 on monocytes [35]. In LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock, leading to the hypothesis that endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses and may behave surprisingly as anti-inflammatory molecules [35]. 3. Cloning of PAF-AH and transcriptional control Human macrophage PAF-AH was cloned by Tjoelker et al. [36]; 12 exons/introns, spanning a 45-kilobase region on chromosome 6, were characterized and a protein of 441 amino acids (45 kDa) having a typical signal sequence and a serine esterase consensus motif, GXSXG was deduced. The cDNA encoding PAFAH was expressed in E. coli and in COS cells and the recombinant protein showed similar enzymatic properties to plasma enzyme [36]. A 3.5-kilobase genomic fragment containing human PAFAH promoter was analyzed next by Cao at al. [37], who showed that a 1.3-kilobase 5′ fragment contained several regulatory elements including a very short 5′-flanking region (72 base pairs) that was sufficient for more than 65% of the basal activity. Numerous consensus sequences for nuclear factors were found including
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
1353
Fig. 2. Cartoon depicting the role of PAF-AH in atherosclerotic plaque formation. PAF-AH is impaired upon LDL oxidation, thus the color changes from orange (active) in native LDL to yellow (less active) in MM-LDL and grey (inactive) in Ox-LDL. Abbreviations: MM-LDL, minimally-oxidized LDL; Ox-LDL, oxidized LDL.
TATA box, STAT, CAAT, Sp1 and MS2 [37]. In promoterluciferase transfection experiments PAF-AH promoter was negatively regulated by interferon γ and LPS, whereas PAF stimulated it via its receptor. Maturation of monocytes into macrophages induces activation of PAF-AH transcription and synthesis [11,24], as this promoter is normally inhibited in monocytes [37]. PAF-AH is transcriptionally upregulated by peroxisome proliferator-activated receptor (PPAR) γ ligands, 15d-PGJ2 and pioglitazone, and its increase prevents PAF-induced cytoskeleton changes in THP-1 cells [38]; however these observational data did not show how PPAR γ transactivates PAF-AH promoter, pointing out that further mechanistic studies are needed. 4. Substrate specificity In contrast to other classical PLA2s that are interfacial enzymes, PAF-AH does not cleave the sn-2 long chain fatty acids, unless heavily oxidized. PAF-AH acts on its substrates in the aqueous phase and for this reason degrades only water soluble phospholipids [39] including PAF, in this case by hydrolyzing its acetate moiety (2 carbons) in the sn-2 position of glycerol [1] (Fig. 1A). PAF-AH degrades also the short-chain sn-2-analogues of phosphatidylcholine up to 5 carbons [40] or medium-length oxidized chains up to 9 carbons [39] (Fig. 1B). These molecules are non-
enzymatically generated upon oxidation of phosphatidylcholine containing a sn-2 polyunsaturated fatty acid, the latter fatty acid is directly truncated into short chain oxidized moieties, among which the 1-pamitoyl-2-oxovaleroyl(5 carbons)-sn-glycero-3-phosphocholine (POVPC) is one of the major compounds of minimallymodified LDL, also found in atherosclerotic lesions [41], and is an equally good substrate for PAF-AH [42]. Recently, a new activity permitting the release of F2-isoprostanes esterified on phospholipids, however much less efficient than that for short chain phospholipids, was ascribed to PAF-AH in vitro and in vivo in PAF-AH transgenic mouse [43]. For the above cited reasons, PAF-AH is considered as a protective mechanism against accumulation of biologically active oxidized phospholipids in the sites of inflammation; however its exact role in atherogenesis and in other inflammatory events remains largely enigmatic as discussed below. 5. PAF-AH in animal models of inflammatory diseases The anti-inflammatory properties of recombinant PAF-AH (rPAF-AH) in animal models were shown first upon its cloning from human macrophages [44]. The infusion of rPAF-AH was tested in numerous animal models of human diseases. In animal studies, rPAF-AH was a potent cardioprotective agent in an in vivo rabbit model of myocardial ischemia–reperfusion injury [45], an enteral administration of rPAF-AH reduced incidence of neonatal
1354
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
necrosing enterocolitis in rats [46] and inhibited airway inflammation and hyperactivity in mouse model of asthma [47]. We showed that manipulating the level of PAF-AH by adenoviral gene transfer of human cDNA diminished macrophage homing to aortic roots in atherosclerosis-prone C57Bl6 apo E−/− mice [48] and the neointima formation (restenosis) induced by a wire-guided denudation of endothelium of the common left carotid of males and females [49]. Interestingly, the spontaneous atherosclerosis in aortic roots of these mice upon 6 weeks after adenoviral PAF-AH transfer was diminished only in males [49]. Further studies showed that a massive adenoviral overexpression of PAF-AH (76- to 140-fold increase of activity in the circulation) in apoE−/− mice, protected all lipoprotein classes from oxidation in vitro, diminished the concentration of oxLDL autoantibodies in plasma of PAF-AH-transfected mice and inhibited foam cell formation by facilitating cholesterol efflux from peritoneal macrophages in an in vitro model [50]. Finally, a local adenoviral overexpression of PAF-AH reduced neointima formation in ballooninjured carotid arteries in cholesterol-fed WNZ rabbits [51] and in nonhyperlipidemic rabbits [52]. One of the rare examples of a possible proatherogenic role for PAF-AH in small animals is a murine model of combined hyperlipidaemia (mice invalidated for both Apobec1 and LDL receptor genes and overexpressing human apoB100), which although did not show significant abnormalities in glucose or insulin metabolism, had elevated levels of the plasma free fatty acids and PAFAH and increased levels of PAF-AH mRNA in liver; such mice kept on chow diet developed large atherosclerotic lesions in aorta, as compared to C57BL/6 wild-type mice that were not affected [53]. From the latter study, it may be concluded that the generation of apoB100 containing lipoproteins (LDL and VLDL) favors PAF-AH synthesis and its association with these proatherogenic lipoproteins. In contrast, overexpression of the human apoA-I in mice raises HDL levels, protects against atherosclerosis [54] and is accompanied by a several-fold increment in PAF-AH levels in HDL [55]. Transgenic overexpression of human apoA-II lead to decreased HDL levels and to concomitant reduction of PAF-AH by about 40%; however did not modify the antioxidative potential of these particles [56]. Substitution of the Arg123–Tyr166 central domain of apoA-I with the helical pair of apoA-II (Ser12–Ala75) neither impaired HDL production nor was crucial for cholesterol influx to HDL, but it was required for PAF-AH activity, reducing oxidative stress in plasma, macrophage homing and early atherosclerosis in apoE knockout mice [57]. Finally, in lecithin:cholesteryl acyltransferase knockout mice, reduction of both HDLcholesterol by 94% and apoA-I by 90% paralleled by a 71% decrease in PAF-AH activity [58]. In dyslipidemic apoE−/− mice with atherosclerotic lesions, the impaired migration of dendritic cells to lymphatic nodes was observed probably due the generation of PAF and PAF-like molecules, as the migration was restored by the i.v. injection of normal human HDL but not by those lacking PAF-AH, i.e. either isolated from subjects bearing a missense mutation (Val279Phe substitution) or chemically-inactivated PAF-AH with a common serine-esterase inhibitor Pefabloc [59]. Recently, a specific inhibitor of PAF-AH was synthesized [60] that will be helpful to decipher the exact contribution of PAFAH into atherosclerosis.
6. Trials with recombinant PAF-AH in humans Pioneering studies of Miwa et al. [61] showed that PAF-AH deficiency in Japanese asthmatic children was associated with respiratory symptoms. Numerous studies concerning participation of PAF to asthma were conducted all over the world, unfortunately the clinical assays with anti-PAF receptor molecules were mostly unsuccessful [62–64]. The availability of safe rPAF-AH permitted human clinical trials in dual phase asthmatic response in a small group of atopic subjects with mild asthma who received 1 mg/kg of rPAF-AH or placebo. A tendency toward a reduction in sputum neutrophils was observed in case of rPAF-AH infusion; however an overall effect on the allergeninduced dual-phase asthmatic response was not significant for this single dose treatment [65]. Another important challenge for PAF-AH clinical usefulness was sepsis where rPAF-AH (1 or 5 mg/kg) was studied in a prospective, randomized, double-blind, placebo-controlled, multicenter trial on 127 patients with severe sepsis, but without established acute respiratory distress syndrome, and showed a marked reduction in a 28-day all-cause mortality [66]. Although rPAF-AH was well tolerated and not antigenic, the latter finding was not further confirmed in the extension of the former study in 1,261 patients with sepsis (643 received rPAF-AH and 618 received placebo) [67]. Finally, 231 patients admitted to the intensive care unit of University Hospital Jena were evaluated for the changes in plasma levels in PAH-AH; since a very large variability in PAF-AH levels upon admission and upon intensive care of these critically ill patients were found, the authors pointed out the difficulty for identifying patients who may benefit from the treatment with rPAFAH [68]. 7. PAF-AH in atherosclerosis As depicted in Fig. 2, PAF-AH is potentially involved in several crucial events implicated in the onset and the progression of atherosclerosis. Since PAF-AH degrades PAF and PAF-like molecules produced upon LDL oxidation and platelet activation, it protects endothelium from the adhesion and transmigration of leukocytes into intima of the arterial wall [48,69]; furthermore it may protect also smooth muscle cells from activation by these bioactive phospholipids. By contrast, lysophospholipids generated by PAF-AH upon hydrolysis of PAF and PAF-like molecules (Fig. 1) may be deleterious to the vessels. The nature of the receptors for such molecules remains uncovered, as yet. Studies of a missense mutation (Val279Phe substitution) in PAF-AH leading to a complete loss of catalytic activity and its protein mass, present in 27% of the Japanese population as heterozygotes and 4% as homozygotes [27], suggest that the lack of PAF-AH is an independent risk factor for coronary artery disease (CAD) [70] and stroke [71]. More recently in a large study involving 2,819 Japanese patients with myocardial infarction and 2,242 controls, the Val279Phe polymorphism was studied together with 111 other polymorphisms in 70 candidate genes; however no association was found with PAF-AH 279Phe allele and myocardial infarction [72]. In Caucasian populations the Val279Phe polymorphism is absent and the role of PAF-AH in cardiovascular
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
disease in these populations is under debate [73,74] since the demonstration that circulating PAF-AH levels were an independent predictor of the risk of CAD in middle-aged hyperlipidemic men [75], whereas this association was weaker in a cohort of initially healthy women [76]. In dyslipidemia, it was shown that atorvastatin, when administered to patients with IIA and IIB dyslipidemia, lowered the activity of PAF-AH in plasma LDL [77]. Furthermore, in IIB and IV dislipidemic patients the administration of fenofibrate attenuated PAF-AH activity associated with apoB-containing lipoproteins but increased those of HDL-associated enzyme [78]. More recently it was shown in a placebo-controlled trial that fluvastatin lowers PAF-AH activity in dense LDL of patients with type 2 diabetes [79]. These results are in agreement with the existence of a strong correlation between PAF-AH and LDL levels. In our recent cross-sectional study [80], the activity of PAF-AH and a panel of inflammatory mediators were measured in plasma of CAD patients and controls. Individuals within the highest quartile of PAF-AH activity had a 1.8-fold increase in CAD risk compared to those in the first quartile and a 3.9-fold increase when individuals receiving statin and ACE-inhibitor medication were excluded. Surprisingly, no correlation was found between PAFAH levels and those of common markers of inflammation. In a prospective, case cohort study of 12,819 apparently healthy middle-aged men and women in the Atherosclerosis Risk In Communities study (ARIC), it was shown in a model adjusted for traditional risk factors, that the association of PAF-AH with CAD did not reach statistical significance [81]. However, for individuals with LDL-cholesterol below the median (130 mg/dL), PAF-AH and CRP were both significantly and independently associated with CAD in fully adjusted models, suggesting that PAF-AH and CRP may be complementary for identifying individuals at high CHD risk who have low LDL-cholesterol [81]. In Caucasian populations 3 non synonymous polymorphisms in the PAF-AH gene were described [82] and among them, the Ala379Val variant expressing an increased Km for the substrate in an in vitro assay with the recombinant protein produced in E. coli. The association of Ala379Val polymorphism with the risk of myocardial infarction was investigated by Abuzeid et al. [83] in a European case-control study, which showed that homozygosity for
1355
the 379Val allele was associated with a lower risk of myocardial infarction. As this genotype is relatively rare (5–6%), it is not a major determinant of the risk of coronary heart disease in the population; however, its association with potentially less active PAF-AH may support a causative, and not consequential, proinflammatory role of PAF-AH. In our recent AtheroGene cohort study, we confirmed that the 379Val allele was less frequent in CAD patients than in controls and moreover it was associated with a lower risk of future cardiovascular events in these patients, suggesting that this allele might be protective against the development of CAD [84]. Moreover the 379Val allele was associated with a weak, but significant increase of plasma PAF-AH activity that was apparently in contradiction with the protective effect of the allele on risk. We hypothesized that the A379V polymorphism exerts a protective effect by modifying the enzyme function towards a less atherogenic form. Next, we participated to the studies on implication of PAF-AH in diabetes and metabolic syndrome in the University Collage London Diabetes And Cardiovascular (UDAC) cohort [85]; the patients with metabolic syndrome had higher PAF-AH levels than controls (P = 0.002) and those in the higher quartile of oxidized LDL/LDL level had the lowest PAF-AH activity (P = 0.003). The UDAC Study failed however to identify a significant effect of A379V genotype on PAF-AH activity, oxidized LDL/LDL levels or risk [85], possibly due to the size of the cohort that was roughly 2-fold smaller that of AtheroGene study [84]. Metabolic syndrome was also studied in a restrained Greek group (60 patients and 110 controls), where PAF-AH activity in plasma was higher in metabolic syndrome individuals but HDL-associated PAF-AH was lower as compared to controls [86]. Finally, the association of PAF-AH mass and activity with calcified coronary plaques in adults was observed in the nested case-control CARDIA study (266 cases and 266 controls; 33– 45 years old) [87]. The studies performed on an older group of Greek individuals with primary hyperlidemia (67 patients and 67 controls) showed a lack of association between carotid intimamedia thickness and both PAF-AH mass and activity [88]; in a similar way in 190 Sicilian individuals with hypercholesterolemia, no association was found between PAF-AH activity, its gene polymorphisms (Arg92His, Ile198Thr, Ala379Val) and carotid intima-media thickness [89].
Fig. 3. Schematic representation of in vivo actions of PAF-AH.
1356
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
The important question remains as to the exact role of PAF-AH in atherogenesis, as PAF-AH may possess a dual pro- and antiinflammatory role, depending on the concentration and the availability of potential substrates [34,90]; however, it may also turn out that PAF-AH is merely a marker of undergoing atherosclerosis. These questions must be answered before undertaking any medication specifically inhibiting PAF-AH in patients with atherosclerosis, as suggested recently by Macphee et al. (review [91]). 8. Conclusions Cloning of PAF-AH has sustained a tremendous promise towards the use of PAF-AH recombinant protein in clinical situations. Unfortunately, neither in asthma nor in sepsis did the recombinant enzyme showed sufficient efficacy, as summarized in Fig. 3. In numerous animal models of inflammation or sepsis rPAF-AH was however efficient, pointing out the extreme difficulty to extrapolate from small animal models to human beings. PAF-AH contribution to human reproduction is equally mostly based on animal studies, thus might be totally different in humans. Last but not least, remains the most challenging question concerning the input of PAF-AH to atherosclerosis, as there is no clear cut picture how this enzyme contributes to this chronic disease.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Acknowledgements This research was supported by the Institut National de la Santé et de la Recherche Médicale, by a Marie Curie Individual Fellowship (E2006DD) and a post-doctoral scholarship from the Fondation pour la Recherche Médicale (FRM: ACE20050703776) to Sonia-Athina Karabina. Ewa Ninio is a Director of Research at the Centre National de la Recherche Scientifique.
[17]
[18]
[19]
References [1] M.L. Blank, T.C. Lee, V. Fitzgerald, F. Snyder, A specific acetylhydrolase for 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (a hypotensive and platelet-activating lipid), J. Biol. Chem. 256 (1981) 175–178. [2] J.M. Heery, M. Kozak, D.M. Stafforini, D.A. Jones, G.A. Zimmerman, T.M. McIntyre, S.M. Prescott, Oxidatively modified LDL contains phospholipids with platelet-activating factor-like activity and stimulates the growth of smooth muscle cells, J. Clin. Invest. 96 (1995) 2322–2330. [3] V.S. Subramanian, J. Goyal, M. Miwa, J. Sugatami, M. Akiyama, M. Liu, P.V. Subbaiah, Role of lecithin-cholesterol acyltransferase in the metabolism of oxidized phospholipids in plasma: studies with platelet-activating factor-acetyl hydrolase-deficient plasma, Bba, Mol. Cell Biol. Lipids 1439 (1999) 95–109. [4] J.A. Berliner, G. Subbanagounder, N. Leitinger, A.D. Watson, D. Vora, Evidence for a role of phospholipid oxidation products in atherogenesis, Trends Cardiovasc. Med. 11 (2001) 142–147. [5] S. Pegorier, D. Stengel, H. Durand, M. Croset, E. Ninio, Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophages Implications in atherosclerosis, Atherosclerosis (in press) (Electronic publication ahead of print). [6] G.K. Marathe, S.M. Prescott, G.A. Zimmerman, T.M. McIntyre, Oxidized LDL contains inflammatory PAF-like phospholipids, Trends Cardiovasc. Med. 11 (2001) 139–142. [7] N. Kume, M.I. Cybulsky, M.A. Gimbrone, Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells, J. Clin. Invest. 90 (1992) 1138–1144. [8] M. Kohno, K. Yokokawa, K. Yasunari, M. Minami, H. Kano, T. Hanehira,
[20]
[21]
[22]
[23]
[24]
[25]
[26]
J. Yoshikawa, Induction by lysophosphatidylcholine, a major phospholipid component of atherogenic lipoproteins, of human coronary artery smooth muscle cell migration, Circulation 98 (1998) 353–359. R. Palmantier, A. Dulioust, H. Maiza, J. Benveniste, E. Ninio, Biosynthesis of paf-acether. XIV. Paf-acether output in murine peritoneal macrophages is regulated by the level of acetylhydrolase, Biochem. Biophys. Res. Commun. 162 (1989) 475–482. K. Nakajima, M. Murakami, R. Yanoshita, Y. Samejima, K. Karasawa, M. Setaka, S. Nojima, I. Kudo, Activated mast cells release extracellular type platelet-activating factor acetylhydrolase that contributes to autocrine inactivation of platelet-activating factor, J. Biol. Chem. 272 (1997) 19708–19713. M.R. Elstad, D.M. Stafforini, T.M. McIntyre, S.M. Prescott, G.A. Zimmerman, Platelet-activating factor acetylhydrolase increase during macrophage differentiation: a novel mechanism that regulates accumulation of platelet-activating factor, J. Biol. Chem. 264 (1989) 8467–8470. R. Korth, J. Bidault, R. Palmantier, J. Benveniste, E. Ninio, Human platelets release a paf-acether: acetylhydrolase similar to that in plasma, Lipids 28 (1993) 193–199. J. Goudevenos, A.D. Tselepis, M.P. Vini, L. Michalis, D.C. Tsoukatos, M. Elisaf, E. Ninio, D.A. Sideris, Platelet-associated and secreted PAFacetylhydrolase activity in patients with stable angina: sequential changes of the enzyme activity after angioplasty, Eur. J. Clin. Investig. 31 (2001) 15–23. K. Asano, S. Okamoto, K. Fukunaga, T. Shiomi, T. Mori, M. Iwata, Y. Ikeda, K. Yamaguchi, Cellular source(S) of platelet-activating-factor acetylhydrolase activity in plasma, Biochem. Biophys. Res. Commun. 261 (1999) 511–514. O. Chami, C. O'Neill, Identification and regulation of the platelet-activating factor acetylhydrolase activity in the mouse uterus in early pregnancy, Reprod. Fertil. Dev. 13 (2001) 367–376. H. Narahara, Y. Nishioka, J.M. Johnston, Secretion of platelet-activating factor acetylhydrolase by human decidual macrophages, J. Clin. Endocrinol. Metab. 77 (1993) 1258–1262. H. Narahara, J.M. Johnston, Effects of endotoxins and cytokines on the secretion of platelet-activating factor-acetylhydrolase by human decidual macrophages, Am. J. Obstet. Gynecol. 169 (1993) 531–537. D.M. Stafforini, T.M. McIntyre, M.E. Carter, S.M. Prescott, Human plasma platelet-activating factor acetylhydrolase: association with lipoprotein particles and role in the degradation of platelet-activating factor, J. Biol. Chem. 262 (1987) 4215–4222. S.A. Karabina, M. Elisaf, E. Bairaktari, C. Tzallas, K.C. Siamopoulos, A.D. Tselepis, Increased activity of platelet-activating factor acetylhydrolase in low-density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia, Eur. J. Clin. Investig. 27 (1997) 595–602. C. Dentan, A.D. Tselepis, M.J. Chapman, E. Ninio, Pefabloc, 4-[2aminiethyl]benzensulfonyl fluoride, is a new, potent, nontoxic and irreversible inhibitor of PAF-degrading acethylhydrolase, Biochim. Biophys. Acta 1299 (1996) 353–357. S. Benitez, J.L. Sanchez-Quesada, V. Ribas, O. Jorba, F. Blanco-Vaca, F. Gonzalez-Sastre, J. Ordonez-Llanos, Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction, Circulation 108 (2003) 92–96. C. Blencowe, A. Hermetter, G.M. Kostner, H.P. Deigner, Enhanced association of platelet-activating factor acetylhydrolase with lipoprotein (a) in comparison with low density lipoprotein, J. Biol. Chem. 270 (1995) 31151–31157. S.A. Karabina, M.C. Elisaf, J. Goudevenos, K.C. Siamopoulos, D. Sideris, A.D. Tselepis, PAF-acetylhydrolase activity of Lp(a) before and during Cu(2+)induced oxidative modification in vitro, Atherosclerosis 125 (1996) 121–134. A.D. Tselepis, S.-A. Karabina, D. Stengel, R. Piédagnel, M.J. Chapman, E. Ninio, N-linked glycosylation of macrophage-derived PAF-AH is a major determinant of enzyme association with plasma HDL, J. Lipid Res. 42 (2002) 1645–1654. A.D. Tselepis, C. Dentan, S.A. Karabina, M.J. Chapman, E. Ninio, PAFdegrading acetylhydrolase is preferentially associated with dense LDL and VHDL-1 in human plasma. Catalytic characteristics and relation to the monocyte-derived enzyme, Arterioscler. Thromb. Vasc. Biol. 15 (1995) 1764–1773. G.K. Marathe, G.A. Zimmerman, T.M. McIntyre, PAF-acetylhydrolase,
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
and not Paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles, J. Biol. Chem. 278 (2003) 3937–3947. D.M. Stafforini, K. Satoh, D.L. Atkinson, L.W. Tjoelker, C. Eberhardt, H. Yoshida, T. Imaizumi, S. Takamatsu, G.A. Zimmerman, T.M. McIntyre, P.W. Gray, S.M. Prescott, Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase, J. Clin. Invest. 97 (1996) 2784–2791. L. Rodrigo, B. Mackness, P.N. Durrington, A. Hernandez, M.I. Mackness, Hydrolysis of platelet-activating factor by human serum paraoxonase, Biochem. J. 354 (2001) 1–7. M. Liu, P.V. Subbaiah, Hydrolysis and transesterification of plateletactivating factor by lecithin-cholesterol acyltransferase, Proc. Natl. Acad. Sci. U. S. A. 91 (1994) 6035–6039. J. Goyal, K. Wang, M. Liu, P.V. Subbaiah, Novel function of lecithincholesterol acyltransferase. Hydrolysis of oxidized polar phospholipids generated during lipoprotein oxidation, J. Biol. Chem. 272 (1997) 16231–16239. M.A. Gijon, C. Perez, E. Mendez, M. Sanchez Crespo, Phospholipase A2 from plasma of patients with septic shock is associated with high-density lipoproteins and C3 anaphylatoxin: some implications for its functional role, Biochem. J. 306 (Pt 1) (1995) 167–175. C. Dentan, P. Lesnik, M.J. Chapman, E. Ninio, Paf-acether-degrading acetylhydrolase in plasma LDL is inactivated by copper- and cellmediated oxidation, Arterioscler. Thromb. 14 (1994) 353–360. G. Ambrosio, A. Oriente, C. Napoli, G. Palumbo, P. Chiariello, G. Marone, M. Condorelli, M. Chiariello, M. Triggiani, Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor, J. Clin. Invest. 93 (1994) 2408–2416. D.C. Tsoukatos, M. Arborati, T. Liapikos, K.L. Clay, R.C. Murphy, M.J. Chapman, E. Ninio, Copper-catalyzed oxidation mediates PAF formation in human LDL subspecies. Protective role of PAF:acetylhydrolase in dense LDL, Arterioscler. Thromb. Vasc. Biol. 17 (1997) 3505–3512. V.N. Bochkov, A. Kadl, J. Huber, F. Gruber, B.R. Binder, N. Leitinger, Protective role of phospholipid oxidation products in endotoxin-induced tissue damage, Nature 419 (2002) 77–81. L.W. Tjoelker, C. Eberhardt, J. Unger, H. Le Trong, G.A. Zimmerman, T.M. McIntyre, D.M. Stafforini, S.M. Prescott, P.W. Gray, Plasma plateletactivating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad, J. Biol. Chem. 43 (1995) 25481–25487. Y. Cao, D.M. Stafforini, G.A. Zimmerman, T.M. McIntyre, S.M. Prescott, Expression of plasma platelet-activating factor acetylhydrolase is transcriptionally regulated by mediators of inflammation, J. Biol. Chem. 273 (1998) 4012–4020. C. Sumita, M. Maeda, Y. Fujio, J. Kim, J. Fujitsu, S. Kasayama, I. Yamamoto, J. Azuma, Pioglitazone induces plasma platelet activating factor-acetylhydrolase and inhibits platelet activating factor-mediated cytoskeletal reorganization in macrophage, Biochim. Biophys. Acta 1673 (2004) 115–121. J.H. Min, M.K. Jain, C. Wilder, L. Paul, R. ApitzCastro, D.C. Aspleaf, M.H. Gelb, Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase, Biochem. USA 38 (1999) 12935–12942. M.L. Wardlow, C.P. Cox, K.E. Meng, D.E. Greene, R.S. Farr, Substrate specificity and partial characterization of the paf-acylhydrolase in human serum that rapidly inactivates platelet-activating factor, J. Immunol. 136 (1986) 3441–3446. G. Subbanagounder, N. Leitinger, D.C. Schwenke, J.W. Wong, H. Lee, C. Rizza, A.D. Watson, K.F. Faull, A.M. Fogelman, J.A. Berliner, Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position, Arterioscler. Thromb. Vasc. Biol. 20 (2000) 2248–2254. K.E. Stremler, D.M. Stafforini, S.M. Prescott, G.A. Zimmerman, T.M. McIntyre, An oxidized derivative of phosphatidylcholine is a substrate for the platelet-activating factor acetylhydrolase from human plasma, J. Biol. Chem. 264 (1989) 5331–5334. D.M. Stafforini, J.R. Sheller, T.S. Blackwell, A. Sapirstein, F.E. Yull, T.M. McIntyre, J.V. Bonventre, S.M. Prescott, L.J. Roberts II, Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases, J. Biol. Chem. 281 (2006) 4616–4623.
1357
[44] L.W. Tjoelker, C. Wilder, C. Eberhardt, D.M. Stafforini, G. Dietsch, B. Schimpf, S. Hooper, H. Letrong, L.S. Cousens, G.A. Zimmerman, Y. Yamada, T.M. McIntyre, S.M. Prescott, P.W. Gray, Anti-inflammatory properties of a platelet-activating factor acetylhydrolase, Nature 374 (1995) 549–553. [45] E.N. Morgan, E.M. Boyle, W. Yun, J.C. Kovacich, T.G. Canty, E. Chi, T.H. Pohlman, E.D. Verrier, Platelet-activating factor acetylhydrolase prevents myocardial ischemia–reperfusion injury, Circulation 100 (1999) 365–368. [46] M.S. Caplan, M. Lickerman, L. Adler, G.N. Dietsch, A. Yu, The role of recombinant platelet-activating factor acetylhydrolase in a neonatal rat model of necrotizing enterocolitis, Pediatr. Res. 42 (1997) 779–783. [47] W.R. Henderson Jr., J. Lu, K.M. Poole, G.N. Dietsch, E.Y. Chi, Recombinant human platelet-activating factor-acetylhydrolase inhibits airway inflammation and hyperreactivity in mouse asthma model, J. Immunol. 164 (2000) 3360–3367. [48] G. Theilmeier, B. De Geest, P.P. Van Veldhoven, D. Stengel, C. Michiels, M. Lox, M. Landeloos, M.J. Chapman, E. Ninio, D. Collen, B. Himpens, P. Holvoet, HDL-associated PAF-AH reduces endothelial adhesiveness in apoE−/− mice, FASEB J. 14 (2000) 2032–2039. [49] R. Quarck, B. De Geest, D. Stengel, A. Mertens, M. Lox, G. Theilmeier, C. Michiels, M. Raes, H. Bult, D. Collen, P. Van Veldhoven, E. Ninio, P. Holvoet, Adenovirus-mediated gene transfer of human platelet-activatingfactor- acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice, Circulation 103 (2001) 2495–2500. [50] H. Noto, M. Hara, K. Karasawa, O.N. Iso, H. Satoh, M. Togo, Y. Hashimoto, Y. Yamada, T. Kosaka, M. Kawamura, S. Kimura, K. Tsukamoto, Human plasma platelet-activating factor acetylhydrolase binds to all the murine lipoproteins, conferring protection against oxidative stress, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 829–835. [51] P. Turunen, J. Jalkanen, T. Heikura, H. Puhakka, J. Karppi, K. Nyyssonen, S. Yla-Herttuala, Adenovirus-mediated gene transfer of Lp-PLA2 reduces LDL degradation and foam cell formation in vitro, J. Lipid Res. 45 (2004) 1633–1639. [52] H. Arakawa, J.Y. Qian, D. Baatar, K. Karasawa, Y. Asada, Y. Sasaguri, E.R. Miller, J.L. Witztum, H. Ueno, Local expression of platelet-activating factor-acetylhydrolase reduces accumulation of oxidized lipoproteins and inhibits inflammation, shear stress-induced thrombosis, and neointima formation in balloon-injured carotid arteries in nonhyperlipidemic rabbits, Circulation 111 (2005) 3302–3309. [53] U. Singh, S. Zhong, M. Xiong, T.B. Li, A. Sniderman, B.B. Teng, Increased plasma non-esterified fatty acids and platelet-activating factor acetylhydrolase are associated with susceptibility to atherosclerosis in mice, Clin. Sci. (Lond.) 106 (2004) 421–432. [54] E.M. Rubin, R.M. Krauss, E.A. Spangler, J.G. Verstuyft, S.M. Clift, Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI, Nature 353 (1991) 265–267. [55] B. De Geest, D. Stengel, M. Landeloos, M. Lox, L. Le Gat, D. Collen, P. Holvoet, E. Ninio, Effect of overexpression of human apo A-I in C57BL/6 and C57BL/6 apo E-deficient mice on 2 lipoprotein-associated enzymes, platelet-activating factor acetylhydrolase and paraoxonase: comparison of adenovirus-mediated human apo A-I gene transfer and human apo A-I transgenesis, Arterioscler. Thromb. Vasc. Biol. 20 (2000) E68–E75. [56] E. Boisfer, D. Stengel, D. Pastier, P.M. Laplaud, N. Dousset, E. Ninio, A.D. Kalopissis, Antioxidant properties of HDL in transgenic mice overexpressing human apolipoprotein A-II, J. Lipid Res. 43 (2002) 732–741. [57] P. Holvoet, K. Peeters, S. Lund-Katz, A. Mertens, P. Verhamme, R. Quarck, D. Stengel, M. Lox, E. Deridder, H. Bernar, M. Nickel, G. Theilmeier, E. Ninio, M.C. Phillips, Arg123–Tyr166 domain of human ApoA-I is critical for HDL-mediated inhibition of macrophage homing and early atherosclerosis in mice, Arterioscler. Thromb. Vasc. Biol. 21 (2001) 1977–1983. [58] T.M. Forte, M.N. Oda, L. Knoff, B. Frei, J. Suh, J.A. Harmony, W.D. Stuart, E.M. Rubin, D.S. Ng, Targeted disruption of the murine lecithin: cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration, J. Lipid Res. 40 (1999) 1276–1283. [59] V. Angeli, J. Llodra, J.X. Rong, K. Satoh, S. Ishii, T. Shimizu, E.A. Fisher, G.J. Randolph, Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization, Immunity 21 (2004) 561–574.
1358
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
[60] J.A. Blackie, J.C. Bloomer, M.J. Brown, H.Y. Cheng, B. Hammond, D.M. Hickey, R.J. Ife, C.A. Leach, V.A. Lewis, C.H. Macphee, K.J. Milliner, K.E. Moores, I.L. Pinto, S.A. Smith, I.G. Stansfield, S.J. Stanway, M.A. Taylor, C.J. Theobald, The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2, Bioorg. Med. Chem. Lett. 13 (2003) 1067–1070. [61] M. Miwa, T. Miyake, T. Yamanaka, J. Sugatani, Y. Suzuki, S. Sakata, Y. Araki, M. Matsumoto, Characterization of serum platelet-activating factor (PAF) acetylhydrolase: correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children, J. Clin. Invest. 82 (1983) 1983–1991. [62] L.M. Kuitert, K.P. Hui, S. Uthayarkumar, W. Burke, A.C. Newland, S. Uden, N.C. Barnes, Effect of the platelet-activating factor antagonist UK74,505 on the early and late response to allergen, Am. Rev. Respir. Dis. 147 (1993) 82–86. [63] A. Freitag, R.M. Watson, G. Matsos, C. Eastwood, P.M. O'Byrne, Effect of a platelet activating factor antagonist, WEB 2086, on allergen induced asthmatic responses, Thorax 48 (1993) 594–598. [64] D.J. Evans, P.J. Barnes, M. Cluzel, B.J. O'Connor, Effects of a potent platelet-activating factor antagonist, SR27417A, on allergen-induced asthmatic responses, Am. J. Respir. Crit. Care Med. 156 (1997) 11–16. [65] N.R. Henig, M.L. Aitken, M.C. Liu, A.S. Yu, W.R. Henderson Jr., Effect of recombinant human platelet-activating factor-acetylhydrolase on allergeninduced asthmatic responses, Am. J. Respir. Crit. Care Med. 162 (2000) 523–527. [66] D.P. Schuster, M. Metzler, S. Opal, S. Lowry, R. Balk, E. Abraham, H. Levy, G. Slotman, E. Coyne, S. Souza, J. Pribble, Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: phase IIb, multicenter, randomized, placebocontrolled, clinical trial, Crit. Care Med. 31 (2003) 1612–1619. [67] S. Opal, P.F. Laterre, E. Abraham, B. Francois, X. Wittebole, S. Lowry, J.F. Dhainaut, B. Warren, T. Dugernier, A. Lopez, M. Sanchez, I. Demeyer, L. Jauregui, J.A. Lorente, W. McGee, K. Reinhart, S. Kljucar, S. Souza, J. Pribble, Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial, Crit. Care Med. 32 (2004) 332–341. [68] R.A. Claus, S. Russwurm, B. Dohrn, M. Bauer, W. Losche, Plasma platelet-activating factor acetylhydrolase activity in critically ill patients, Crit. Care Med. 33 (2005) 1416–1419. [69] C. Lee, F. Sigari, T. Segrado, S. Horkko, S. Hama, P.V. Subbaiah, M. Miwa, M. Navab, J.L. Witztum, P.D. Reaven, All ApoB-containing lipoproteins induce monocyte chemotaxis and adhesion when minimally modified. Modulation of lipoprotein bioactivity by platelet-activating factor acetylhydrolase, Arterioscler. Thromb. Vasc. Biol. 19 (1999) 1437–1446. [70] Y. Yamada, S. Ichihara, T. Fujimura, M. Yokota, Identification of the G994/T missence mutation in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men, Metabolism 47 (1998) 177–181. [71] M. Hiramoto, H. Yoshida, T. Imaizumi, N. Yoshimizu, K. Satoh, A mutation in plasma platelet-activating factor acetylhydrolase (Val279(Phe), is a genetic risk factor for stroke, Stroke 28 (1997) 2417–2420. [72] Y. Yamada, H. Izawa, S. Ichihara, F. Takatsu, H. Ishihara, H. Hirayama, T. Sone, M. Tanaka, M. Yokota, Prediction of the risk of myocardial infarction from polymorphisms in candidate genes, N. Engl. J. Med. 347 (2002) 1916–1923. [73] M.J. Caslake, C.J. Packard, Lipoprotein-associated phospholipase A(2) as a biomarker for coronary disease and stroke, Nat. Clin. Pract. Cardiovasc. Med. 2 (2005) 529–535. [74] E. Ninio, Phospholipid mediators in the vessel wall: involvement in atherosclerosis, Curr. Opin. Clin. Nutr. Metab. Care 8 (2005) 123–131. [75] C.J. Packard, D.S. O'Reilly, M.J. Caslake, A.D. McMahon, I. Ford, J. Cooney, C.H. Macphee, K.E. Suckling, M. Krishna, F.E. Wilkinson, A. Rumley, G.D. Lowe, Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group, N. Engl. J. Med. 343 (2000) 1148–1155.
[76] G.J. Blake, N. Dada, J.C. Fox, J.E. Manson, P.M. Ridker, A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women, J. Am. Coll. Cardiol. 38 (2001) 1302–1306. [77] V. Tsimihodimos, S.A. Karabina, A.P. Tambaki, E. Bairaktari, G. Miltiadous, J.A. Goudevenos, M.A. Cariolou, M.J. Chapman, A.D. Tselepis, M. Elisaf, Altered distribution of platelet-activating factor- acetylhydrolase activity between LDL and HDL as a function of the severity of hypercholesterolemia, J. Lipid Res. 43 (2002) 256–263. [78] V. Tsimihodimos, A. Kakafika, A.P. Tambaki, E. Bairaktari, M.J. Chapman, M. Elisaf, A.D. Tselepis, Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apoB-containing lipoproteins, J. Lipid Res. 44 (2003) 927–934. [79] K. Winkler, C. Abletshauser, I. Friedrich, M.M. Hoffmann, H. Wieland, W. Marz, Fluvastatin slow-release lowers platelet-activating factor acetyl hydrolase activity: a placebo-controlled trial in patients with type 2 diabetes, J. Clin. Endocrinol. Metab. 89 (2004) 1153–1159. [80] S. Blankenberg, D. Stengel, H. Rupprecht, C. Bickel, J. Meyer, F. Cambien, L. Tiret, E. Ninio, Plasma PAF-acetylhydrolase in patients with coronary artery disease. Results of a cross-sectional analysis, J. Lipid Res. 44 (2003) 1381–1386. [81] C.M. Ballantyne, R.C. Hoogeveen, H. Bang, J. Coresh, A.R. Folsom, G. Heiss, A.R. Sharrett, Lipoprotein-associated phospholipase A2, highsensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, Circulation 109 (2004) 837–842. [82] S. Kruse, X.-Q. Mao, A. Heinzman, S. Blattmann, M.H. Roberts, S. Braun, P.-S. Gao, J. Forster, J. Kuehr, J.M. Hopkins, T. Shirakawa, K.A. Deichman, The Ile198Thr and Ala379Val variants of plasmatic Paf-acetylhydrolase impair catalytical activities and are associated with atopy and asthma, Am. J. Hum. Genet. 66 (2000) 1522–1530. [83] A.M. Abuzeid, E. Hawe, S.E. Humphries, P.J. Talmud, Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe, Atherosclerosis 168 (2003) 283–288. [84] E. Ninio, D. Tregouet, J.L. Carrier, D. Stengel, C. Bickel, C. Perret, H.J. Rupprecht, F. Cambien, S. Blankenberg, L. Tiret, Platelet-activating factoracetylhydrolase and PAF-receptor gene haplotypes in relation to future cardiovascular event in patients with coronary artery disease, Hum. Mol. Genet. 13 (2004) 1341–1351. [85] P.T. Wootton, J.W. Stephens, S.J. Hurel, H. Durand, J. Cooper, E. Ninio, S.E. Humphries, P.J. Taimud, Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus, Atherosclerosis (in press) (Electronic publication ahead of print). [86] E. Rizos, A.P. Tambaki, I. Gazi, A.D. Tselepis, M. Elisaf, Lipoproteinassociated PAF-acetylhydrolase activity in subjects with the metabolic syndrome, Prostaglandins Leukot. Essent. Fat. Acids 72 (2005) 203–209. [87] C. Iribarren, M.D. Gross, J.A. Darbinian, D.R. Jacobs Jr., S. Sidney, C.M. Loria, Association of lipoprotein-associated phospholipase A2 mass and activity with calcified coronary plaque in young adults: the CARDIA study, Arterioscler. Thromb. Vasc. Biol. 25 (2005) 216–221. [88] D.N. Kiortsis, S. Tsouli, E.S. Lourida, V. Xydis, M.I. Argyropoulou, M. Elisaf, A.D. Tselepis, Lack of association between carotid intimamedia thickness and PAF-acetylhydrolase mass and activity in patients with primary hyperlipidemia, Angiology 56 (2005) 451–458. [89] S. Campo, M.A. Sardo, A. Bitto, A. Bonaiuto, G. Trimarchi, M. Bonaiuto, M. Castaldo, C. Saitta, S. Cristadoro, A. Saitta, Platelet-activating factor acetylhydrolase is not associated with carotid intima-media thickness in hypercholesterolemic Sicilian individuals, Clin. Chem. 50 (2004) 2077–2082. [90] D.C. Tsoukatos, T.A. Liapikos, A.D. Tselepis, M.J. Chapman, E. Ninio, Platelet-activating factor acetylhydrolase and transacetylase activities in human plasma low-density lipoprotein, Biochem. J. 357 (2001) 457–464. [91] C.H. Macphee, J. Nelson, A. Zalewski, Role of lipoprotein-associated phospholipase A(2) in atherosclerosis and its potential as a therapeutic target, Curr. Opin. Pharmacol. 6 (2006) 154–161.
Review
Plasma PAF-acetylhydrolase: An unfulfilled promise? Sonia-Athina Karabina, Ewa Ninio ⁎ INSERM U525, Université Pierre et Marie Curie-Paris6, Faculté de Médecine Pierre et Marie Curie, 91, bd de l’Hôpital 75634 Paris cedex 13, France Received 30 March 2006; received in revised form 4 May 2006; accepted 8 May 2006 Available online 23 May 2006
Abstract Plasma Platelet-activating-Factor (PAF)-acetylhydrolase (PAF-AH also named lipoprotein-PLA2 or PLA2G7 gene) is secreted by macrophages, it degrades PAF and oxidation products of phosphatidylcholine produced upon LDL oxidation and/or oxidative stress, and thus is considered as a potentially anti-inflammatory enzyme. Cloning of PAF-AH has sustained tremendous promises towards the use of PAF-AH recombinant protein in clinical situations. The reason for that stems from the numerous animal models of inflammation, atherosclerosis or sepsis, where raising the levels of circulating PAF-AH either through recombinant protein infusion or through the adenoviral gene transfer showed to be beneficial. Unfortunately, neither in human asthma nor in sepsis the recombinant PAF-AH showed sufficient efficacy. One of the most challenging questions nowadays is as to whether PAF-AH is pro- or anti-atherogenic in humans, as PAF-AH may possess a dual pro- and anti-inflammatory role, depending on the concentration and the availability of potential substrates. It is equally possible that the plasma level of PAF-AH is a diagnostic marker of ongoing atherosclerosis. © 2006 Elsevier B.V. All rights reserved. Keywords: PAF-AH; Lp-PLA2; LDL-PLA2; PLA2; Oxidized phospholipid; Inflammation; Atherogenesis
1. Introduction Over the past years, a substantial amount of research has focused on an unusual secretory Ca2+-independent phospholipase A2 (PLA2) belonging to the group VIIA, the plasma Platelet-activating-Factor (PAF)-acetylhydrolase (PAF-AH also named lipoprotein-PLA2 or PLA2G7 gene) which degrades PAF [1] (Fig. 1A) and the oxidation products of phosphatidylcholine [2,3] (Fig. 1B). Phosphatidylcholine containing arachidonate at the sn-2 position of glycerol is abundant in low density lipoproteins (LDL) and upon oxidation gives raise to numerous oxidized products with short chains at sn-2 position of glycerol. Such truncated oxidized phospholipids were either isolated from oxidized LDL (oxLDL) or
produced upon oxidation of synthetic 1-palmitoyl-2-arachidonylsn-glycero-3-phosphatidylcholine (oxPAPC) and further functionally characterized in cell culture [4]. Some of these molecules express PAF-like activity, as their effects are attenuated by the specific PAF antagonists [5] and they are degraded by plasma PAFAH [6]. The degradation products of oxPAPC and PAF, mediated by PAF-AH, namely the lysophosphatidylcholine (lyso-PC) and lyso-PAF and short chain fatty acids, may possess deleterious properties on the vessel wall [7,8]. Finally, numerous proinflammatory cells produce and secrete PAF. The purpose of the current review is to summarize the latest views on plasma PAF-AH and its implications in inflammation and in atherosclerosis. 2. Cellular sources and association with lipoproteins
Abbreviations: CAD, coronary artery disease; HDL, high density lipoproteins; LDL, low density lipoproteins; LPS, lipopolysaccharide; Lyso-PAF, lyso-Plateletactivating-factor; Lyso-PC, lysophosphatidylcholine; oxLDL, oxidized LDL; oxPAPC, oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphatidylcholine; PC, phosphatidylcholine; PLA2, phospholipase A2; POVPC, 1-pamitoyl-2oxovaleroyl(5 carbons)-sn-glycero-3-phosphocholine; PPARγ, peroxisome proliferator-activated receptor γ; PAF, Platelet-activating-Factor; rPAF-AH, recombinant PAF-AH ⁎ Corresponding author. Tel.: +1 331 40 77 97 68; fax: +1 331 40 77 97 68. E-mail address: [email protected] (E. Ninio). 1388-1981/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2006.05.008
Mature murine macrophages [9], antigen-activated bone-marrow-derived and serosal mast cells [10] and human mature macrophages [11] and activated platelets [12,13] synthesize and excrete active PAF-AH (Fig. 2); a myeloid origin of this enzyme was confirmed later by showing that the recipients of bone marrow transplantation from PAF-AH deficient donors (Val279Phe substitution) became also deficient [14]. In early pregnancy in mice, PAF-AH was found in uterine endometrium and luminal fluids and
1352
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
Fig. 1. Degradation of PAF into lyso-PAF (A) and oxidized PC into lyso-PC (B) by PAF-AH; n = 14 to 16.
had the same biochemical characteristics as the plasma form of the enzyme and its source was plasma [15]. Secretion of PAF-AH was also described from human decidual macrophages suggesting its role in parturition [16]; moreover lipopolysaccharide (LPS) inhibited PAF-AH secretion suggesting that the resulting accumulation of PAF may be involved in preterm labor caused by endotoxin [17]. Secreted PAF-AH is mainly associated with LDL and to lesser extent with high density lipoproteins (HDL) [18]; its association with small dense LDL particles [19,20] and with electronegative LDL subfractions was documented [21]. In plasma rich in lipoprotein (a), PAF-AH has a tendency to bind to this unusual and pro-atherogenic lipoprotein [22,23]. Among plasma lipoproteins only HDL are endowed with antiatherogenic and anti-inflammatory properties. We have shown that the macrophage PAF-AH is highly glycosylated and for this reason it is relatively poorly associated with human HDL [24], as only 20 to 30% of the total plasma activity is recovered in these particles [18,25]. PAF-AH is probably the unique enzyme in HDL endowed with PLA2 activity towards PAF and PAF-like molecules [26]; plasma isolated from subjects bearing a missense mutation (Val279Phe substitution) in exon 9 of PAF-AH, leading to a complete loss of PAF-AH catalytic activity [27], hydrolyzes neither PAF nor its analogues and is no longer protective against oxidation [26]. However, this plasma contains intact activities of both paraoxonase and lecithin-cholesterol acyltransferase that were claimed to hydrolyze PAF in vitro [3,28–30]. Presently it cannot be excluded that upon inflammation other secretory PLA2 could be secreted and transported on HDL [31].
Of interest, the oxidation process severely inhibits PAF-AH [32,33] and permits accumulation of PAF and oxidized truncated phospholipids with PAF activity [34] (Fig. 2). Accumulation of such oxidized phospholipids in some circumstances may inhibit LPS-induced NFκB-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14 on monocytes [35]. In LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock, leading to the hypothesis that endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses and may behave surprisingly as anti-inflammatory molecules [35]. 3. Cloning of PAF-AH and transcriptional control Human macrophage PAF-AH was cloned by Tjoelker et al. [36]; 12 exons/introns, spanning a 45-kilobase region on chromosome 6, were characterized and a protein of 441 amino acids (45 kDa) having a typical signal sequence and a serine esterase consensus motif, GXSXG was deduced. The cDNA encoding PAFAH was expressed in E. coli and in COS cells and the recombinant protein showed similar enzymatic properties to plasma enzyme [36]. A 3.5-kilobase genomic fragment containing human PAFAH promoter was analyzed next by Cao at al. [37], who showed that a 1.3-kilobase 5′ fragment contained several regulatory elements including a very short 5′-flanking region (72 base pairs) that was sufficient for more than 65% of the basal activity. Numerous consensus sequences for nuclear factors were found including
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
1353
Fig. 2. Cartoon depicting the role of PAF-AH in atherosclerotic plaque formation. PAF-AH is impaired upon LDL oxidation, thus the color changes from orange (active) in native LDL to yellow (less active) in MM-LDL and grey (inactive) in Ox-LDL. Abbreviations: MM-LDL, minimally-oxidized LDL; Ox-LDL, oxidized LDL.
TATA box, STAT, CAAT, Sp1 and MS2 [37]. In promoterluciferase transfection experiments PAF-AH promoter was negatively regulated by interferon γ and LPS, whereas PAF stimulated it via its receptor. Maturation of monocytes into macrophages induces activation of PAF-AH transcription and synthesis [11,24], as this promoter is normally inhibited in monocytes [37]. PAF-AH is transcriptionally upregulated by peroxisome proliferator-activated receptor (PPAR) γ ligands, 15d-PGJ2 and pioglitazone, and its increase prevents PAF-induced cytoskeleton changes in THP-1 cells [38]; however these observational data did not show how PPAR γ transactivates PAF-AH promoter, pointing out that further mechanistic studies are needed. 4. Substrate specificity In contrast to other classical PLA2s that are interfacial enzymes, PAF-AH does not cleave the sn-2 long chain fatty acids, unless heavily oxidized. PAF-AH acts on its substrates in the aqueous phase and for this reason degrades only water soluble phospholipids [39] including PAF, in this case by hydrolyzing its acetate moiety (2 carbons) in the sn-2 position of glycerol [1] (Fig. 1A). PAF-AH degrades also the short-chain sn-2-analogues of phosphatidylcholine up to 5 carbons [40] or medium-length oxidized chains up to 9 carbons [39] (Fig. 1B). These molecules are non-
enzymatically generated upon oxidation of phosphatidylcholine containing a sn-2 polyunsaturated fatty acid, the latter fatty acid is directly truncated into short chain oxidized moieties, among which the 1-pamitoyl-2-oxovaleroyl(5 carbons)-sn-glycero-3-phosphocholine (POVPC) is one of the major compounds of minimallymodified LDL, also found in atherosclerotic lesions [41], and is an equally good substrate for PAF-AH [42]. Recently, a new activity permitting the release of F2-isoprostanes esterified on phospholipids, however much less efficient than that for short chain phospholipids, was ascribed to PAF-AH in vitro and in vivo in PAF-AH transgenic mouse [43]. For the above cited reasons, PAF-AH is considered as a protective mechanism against accumulation of biologically active oxidized phospholipids in the sites of inflammation; however its exact role in atherogenesis and in other inflammatory events remains largely enigmatic as discussed below. 5. PAF-AH in animal models of inflammatory diseases The anti-inflammatory properties of recombinant PAF-AH (rPAF-AH) in animal models were shown first upon its cloning from human macrophages [44]. The infusion of rPAF-AH was tested in numerous animal models of human diseases. In animal studies, rPAF-AH was a potent cardioprotective agent in an in vivo rabbit model of myocardial ischemia–reperfusion injury [45], an enteral administration of rPAF-AH reduced incidence of neonatal
1354
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
necrosing enterocolitis in rats [46] and inhibited airway inflammation and hyperactivity in mouse model of asthma [47]. We showed that manipulating the level of PAF-AH by adenoviral gene transfer of human cDNA diminished macrophage homing to aortic roots in atherosclerosis-prone C57Bl6 apo E−/− mice [48] and the neointima formation (restenosis) induced by a wire-guided denudation of endothelium of the common left carotid of males and females [49]. Interestingly, the spontaneous atherosclerosis in aortic roots of these mice upon 6 weeks after adenoviral PAF-AH transfer was diminished only in males [49]. Further studies showed that a massive adenoviral overexpression of PAF-AH (76- to 140-fold increase of activity in the circulation) in apoE−/− mice, protected all lipoprotein classes from oxidation in vitro, diminished the concentration of oxLDL autoantibodies in plasma of PAF-AH-transfected mice and inhibited foam cell formation by facilitating cholesterol efflux from peritoneal macrophages in an in vitro model [50]. Finally, a local adenoviral overexpression of PAF-AH reduced neointima formation in ballooninjured carotid arteries in cholesterol-fed WNZ rabbits [51] and in nonhyperlipidemic rabbits [52]. One of the rare examples of a possible proatherogenic role for PAF-AH in small animals is a murine model of combined hyperlipidaemia (mice invalidated for both Apobec1 and LDL receptor genes and overexpressing human apoB100), which although did not show significant abnormalities in glucose or insulin metabolism, had elevated levels of the plasma free fatty acids and PAFAH and increased levels of PAF-AH mRNA in liver; such mice kept on chow diet developed large atherosclerotic lesions in aorta, as compared to C57BL/6 wild-type mice that were not affected [53]. From the latter study, it may be concluded that the generation of apoB100 containing lipoproteins (LDL and VLDL) favors PAF-AH synthesis and its association with these proatherogenic lipoproteins. In contrast, overexpression of the human apoA-I in mice raises HDL levels, protects against atherosclerosis [54] and is accompanied by a several-fold increment in PAF-AH levels in HDL [55]. Transgenic overexpression of human apoA-II lead to decreased HDL levels and to concomitant reduction of PAF-AH by about 40%; however did not modify the antioxidative potential of these particles [56]. Substitution of the Arg123–Tyr166 central domain of apoA-I with the helical pair of apoA-II (Ser12–Ala75) neither impaired HDL production nor was crucial for cholesterol influx to HDL, but it was required for PAF-AH activity, reducing oxidative stress in plasma, macrophage homing and early atherosclerosis in apoE knockout mice [57]. Finally, in lecithin:cholesteryl acyltransferase knockout mice, reduction of both HDLcholesterol by 94% and apoA-I by 90% paralleled by a 71% decrease in PAF-AH activity [58]. In dyslipidemic apoE−/− mice with atherosclerotic lesions, the impaired migration of dendritic cells to lymphatic nodes was observed probably due the generation of PAF and PAF-like molecules, as the migration was restored by the i.v. injection of normal human HDL but not by those lacking PAF-AH, i.e. either isolated from subjects bearing a missense mutation (Val279Phe substitution) or chemically-inactivated PAF-AH with a common serine-esterase inhibitor Pefabloc [59]. Recently, a specific inhibitor of PAF-AH was synthesized [60] that will be helpful to decipher the exact contribution of PAFAH into atherosclerosis.
6. Trials with recombinant PAF-AH in humans Pioneering studies of Miwa et al. [61] showed that PAF-AH deficiency in Japanese asthmatic children was associated with respiratory symptoms. Numerous studies concerning participation of PAF to asthma were conducted all over the world, unfortunately the clinical assays with anti-PAF receptor molecules were mostly unsuccessful [62–64]. The availability of safe rPAF-AH permitted human clinical trials in dual phase asthmatic response in a small group of atopic subjects with mild asthma who received 1 mg/kg of rPAF-AH or placebo. A tendency toward a reduction in sputum neutrophils was observed in case of rPAF-AH infusion; however an overall effect on the allergeninduced dual-phase asthmatic response was not significant for this single dose treatment [65]. Another important challenge for PAF-AH clinical usefulness was sepsis where rPAF-AH (1 or 5 mg/kg) was studied in a prospective, randomized, double-blind, placebo-controlled, multicenter trial on 127 patients with severe sepsis, but without established acute respiratory distress syndrome, and showed a marked reduction in a 28-day all-cause mortality [66]. Although rPAF-AH was well tolerated and not antigenic, the latter finding was not further confirmed in the extension of the former study in 1,261 patients with sepsis (643 received rPAF-AH and 618 received placebo) [67]. Finally, 231 patients admitted to the intensive care unit of University Hospital Jena were evaluated for the changes in plasma levels in PAH-AH; since a very large variability in PAF-AH levels upon admission and upon intensive care of these critically ill patients were found, the authors pointed out the difficulty for identifying patients who may benefit from the treatment with rPAFAH [68]. 7. PAF-AH in atherosclerosis As depicted in Fig. 2, PAF-AH is potentially involved in several crucial events implicated in the onset and the progression of atherosclerosis. Since PAF-AH degrades PAF and PAF-like molecules produced upon LDL oxidation and platelet activation, it protects endothelium from the adhesion and transmigration of leukocytes into intima of the arterial wall [48,69]; furthermore it may protect also smooth muscle cells from activation by these bioactive phospholipids. By contrast, lysophospholipids generated by PAF-AH upon hydrolysis of PAF and PAF-like molecules (Fig. 1) may be deleterious to the vessels. The nature of the receptors for such molecules remains uncovered, as yet. Studies of a missense mutation (Val279Phe substitution) in PAF-AH leading to a complete loss of catalytic activity and its protein mass, present in 27% of the Japanese population as heterozygotes and 4% as homozygotes [27], suggest that the lack of PAF-AH is an independent risk factor for coronary artery disease (CAD) [70] and stroke [71]. More recently in a large study involving 2,819 Japanese patients with myocardial infarction and 2,242 controls, the Val279Phe polymorphism was studied together with 111 other polymorphisms in 70 candidate genes; however no association was found with PAF-AH 279Phe allele and myocardial infarction [72]. In Caucasian populations the Val279Phe polymorphism is absent and the role of PAF-AH in cardiovascular
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
disease in these populations is under debate [73,74] since the demonstration that circulating PAF-AH levels were an independent predictor of the risk of CAD in middle-aged hyperlipidemic men [75], whereas this association was weaker in a cohort of initially healthy women [76]. In dyslipidemia, it was shown that atorvastatin, when administered to patients with IIA and IIB dyslipidemia, lowered the activity of PAF-AH in plasma LDL [77]. Furthermore, in IIB and IV dislipidemic patients the administration of fenofibrate attenuated PAF-AH activity associated with apoB-containing lipoproteins but increased those of HDL-associated enzyme [78]. More recently it was shown in a placebo-controlled trial that fluvastatin lowers PAF-AH activity in dense LDL of patients with type 2 diabetes [79]. These results are in agreement with the existence of a strong correlation between PAF-AH and LDL levels. In our recent cross-sectional study [80], the activity of PAF-AH and a panel of inflammatory mediators were measured in plasma of CAD patients and controls. Individuals within the highest quartile of PAF-AH activity had a 1.8-fold increase in CAD risk compared to those in the first quartile and a 3.9-fold increase when individuals receiving statin and ACE-inhibitor medication were excluded. Surprisingly, no correlation was found between PAFAH levels and those of common markers of inflammation. In a prospective, case cohort study of 12,819 apparently healthy middle-aged men and women in the Atherosclerosis Risk In Communities study (ARIC), it was shown in a model adjusted for traditional risk factors, that the association of PAF-AH with CAD did not reach statistical significance [81]. However, for individuals with LDL-cholesterol below the median (130 mg/dL), PAF-AH and CRP were both significantly and independently associated with CAD in fully adjusted models, suggesting that PAF-AH and CRP may be complementary for identifying individuals at high CHD risk who have low LDL-cholesterol [81]. In Caucasian populations 3 non synonymous polymorphisms in the PAF-AH gene were described [82] and among them, the Ala379Val variant expressing an increased Km for the substrate in an in vitro assay with the recombinant protein produced in E. coli. The association of Ala379Val polymorphism with the risk of myocardial infarction was investigated by Abuzeid et al. [83] in a European case-control study, which showed that homozygosity for
1355
the 379Val allele was associated with a lower risk of myocardial infarction. As this genotype is relatively rare (5–6%), it is not a major determinant of the risk of coronary heart disease in the population; however, its association with potentially less active PAF-AH may support a causative, and not consequential, proinflammatory role of PAF-AH. In our recent AtheroGene cohort study, we confirmed that the 379Val allele was less frequent in CAD patients than in controls and moreover it was associated with a lower risk of future cardiovascular events in these patients, suggesting that this allele might be protective against the development of CAD [84]. Moreover the 379Val allele was associated with a weak, but significant increase of plasma PAF-AH activity that was apparently in contradiction with the protective effect of the allele on risk. We hypothesized that the A379V polymorphism exerts a protective effect by modifying the enzyme function towards a less atherogenic form. Next, we participated to the studies on implication of PAF-AH in diabetes and metabolic syndrome in the University Collage London Diabetes And Cardiovascular (UDAC) cohort [85]; the patients with metabolic syndrome had higher PAF-AH levels than controls (P = 0.002) and those in the higher quartile of oxidized LDL/LDL level had the lowest PAF-AH activity (P = 0.003). The UDAC Study failed however to identify a significant effect of A379V genotype on PAF-AH activity, oxidized LDL/LDL levels or risk [85], possibly due to the size of the cohort that was roughly 2-fold smaller that of AtheroGene study [84]. Metabolic syndrome was also studied in a restrained Greek group (60 patients and 110 controls), where PAF-AH activity in plasma was higher in metabolic syndrome individuals but HDL-associated PAF-AH was lower as compared to controls [86]. Finally, the association of PAF-AH mass and activity with calcified coronary plaques in adults was observed in the nested case-control CARDIA study (266 cases and 266 controls; 33– 45 years old) [87]. The studies performed on an older group of Greek individuals with primary hyperlidemia (67 patients and 67 controls) showed a lack of association between carotid intimamedia thickness and both PAF-AH mass and activity [88]; in a similar way in 190 Sicilian individuals with hypercholesterolemia, no association was found between PAF-AH activity, its gene polymorphisms (Arg92His, Ile198Thr, Ala379Val) and carotid intima-media thickness [89].
Fig. 3. Schematic representation of in vivo actions of PAF-AH.
1356
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
The important question remains as to the exact role of PAF-AH in atherogenesis, as PAF-AH may possess a dual pro- and antiinflammatory role, depending on the concentration and the availability of potential substrates [34,90]; however, it may also turn out that PAF-AH is merely a marker of undergoing atherosclerosis. These questions must be answered before undertaking any medication specifically inhibiting PAF-AH in patients with atherosclerosis, as suggested recently by Macphee et al. (review [91]). 8. Conclusions Cloning of PAF-AH has sustained a tremendous promise towards the use of PAF-AH recombinant protein in clinical situations. Unfortunately, neither in asthma nor in sepsis did the recombinant enzyme showed sufficient efficacy, as summarized in Fig. 3. In numerous animal models of inflammation or sepsis rPAF-AH was however efficient, pointing out the extreme difficulty to extrapolate from small animal models to human beings. PAF-AH contribution to human reproduction is equally mostly based on animal studies, thus might be totally different in humans. Last but not least, remains the most challenging question concerning the input of PAF-AH to atherosclerosis, as there is no clear cut picture how this enzyme contributes to this chronic disease.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
Acknowledgements This research was supported by the Institut National de la Santé et de la Recherche Médicale, by a Marie Curie Individual Fellowship (E2006DD) and a post-doctoral scholarship from the Fondation pour la Recherche Médicale (FRM: ACE20050703776) to Sonia-Athina Karabina. Ewa Ninio is a Director of Research at the Centre National de la Recherche Scientifique.
[17]
[18]
[19]
References [1] M.L. Blank, T.C. Lee, V. Fitzgerald, F. Snyder, A specific acetylhydrolase for 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (a hypotensive and platelet-activating lipid), J. Biol. Chem. 256 (1981) 175–178. [2] J.M. Heery, M. Kozak, D.M. Stafforini, D.A. Jones, G.A. Zimmerman, T.M. McIntyre, S.M. Prescott, Oxidatively modified LDL contains phospholipids with platelet-activating factor-like activity and stimulates the growth of smooth muscle cells, J. Clin. Invest. 96 (1995) 2322–2330. [3] V.S. Subramanian, J. Goyal, M. Miwa, J. Sugatami, M. Akiyama, M. Liu, P.V. Subbaiah, Role of lecithin-cholesterol acyltransferase in the metabolism of oxidized phospholipids in plasma: studies with platelet-activating factor-acetyl hydrolase-deficient plasma, Bba, Mol. Cell Biol. Lipids 1439 (1999) 95–109. [4] J.A. Berliner, G. Subbanagounder, N. Leitinger, A.D. Watson, D. Vora, Evidence for a role of phospholipid oxidation products in atherogenesis, Trends Cardiovasc. Med. 11 (2001) 142–147. [5] S. Pegorier, D. Stengel, H. Durand, M. Croset, E. Ninio, Oxidized phospholipid: POVPC binds to platelet-activating-factor receptor on human macrophages Implications in atherosclerosis, Atherosclerosis (in press) (Electronic publication ahead of print). [6] G.K. Marathe, S.M. Prescott, G.A. Zimmerman, T.M. McIntyre, Oxidized LDL contains inflammatory PAF-like phospholipids, Trends Cardiovasc. Med. 11 (2001) 139–142. [7] N. Kume, M.I. Cybulsky, M.A. Gimbrone, Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells, J. Clin. Invest. 90 (1992) 1138–1144. [8] M. Kohno, K. Yokokawa, K. Yasunari, M. Minami, H. Kano, T. Hanehira,
[20]
[21]
[22]
[23]
[24]
[25]
[26]
J. Yoshikawa, Induction by lysophosphatidylcholine, a major phospholipid component of atherogenic lipoproteins, of human coronary artery smooth muscle cell migration, Circulation 98 (1998) 353–359. R. Palmantier, A. Dulioust, H. Maiza, J. Benveniste, E. Ninio, Biosynthesis of paf-acether. XIV. Paf-acether output in murine peritoneal macrophages is regulated by the level of acetylhydrolase, Biochem. Biophys. Res. Commun. 162 (1989) 475–482. K. Nakajima, M. Murakami, R. Yanoshita, Y. Samejima, K. Karasawa, M. Setaka, S. Nojima, I. Kudo, Activated mast cells release extracellular type platelet-activating factor acetylhydrolase that contributes to autocrine inactivation of platelet-activating factor, J. Biol. Chem. 272 (1997) 19708–19713. M.R. Elstad, D.M. Stafforini, T.M. McIntyre, S.M. Prescott, G.A. Zimmerman, Platelet-activating factor acetylhydrolase increase during macrophage differentiation: a novel mechanism that regulates accumulation of platelet-activating factor, J. Biol. Chem. 264 (1989) 8467–8470. R. Korth, J. Bidault, R. Palmantier, J. Benveniste, E. Ninio, Human platelets release a paf-acether: acetylhydrolase similar to that in plasma, Lipids 28 (1993) 193–199. J. Goudevenos, A.D. Tselepis, M.P. Vini, L. Michalis, D.C. Tsoukatos, M. Elisaf, E. Ninio, D.A. Sideris, Platelet-associated and secreted PAFacetylhydrolase activity in patients with stable angina: sequential changes of the enzyme activity after angioplasty, Eur. J. Clin. Investig. 31 (2001) 15–23. K. Asano, S. Okamoto, K. Fukunaga, T. Shiomi, T. Mori, M. Iwata, Y. Ikeda, K. Yamaguchi, Cellular source(S) of platelet-activating-factor acetylhydrolase activity in plasma, Biochem. Biophys. Res. Commun. 261 (1999) 511–514. O. Chami, C. O'Neill, Identification and regulation of the platelet-activating factor acetylhydrolase activity in the mouse uterus in early pregnancy, Reprod. Fertil. Dev. 13 (2001) 367–376. H. Narahara, Y. Nishioka, J.M. Johnston, Secretion of platelet-activating factor acetylhydrolase by human decidual macrophages, J. Clin. Endocrinol. Metab. 77 (1993) 1258–1262. H. Narahara, J.M. Johnston, Effects of endotoxins and cytokines on the secretion of platelet-activating factor-acetylhydrolase by human decidual macrophages, Am. J. Obstet. Gynecol. 169 (1993) 531–537. D.M. Stafforini, T.M. McIntyre, M.E. Carter, S.M. Prescott, Human plasma platelet-activating factor acetylhydrolase: association with lipoprotein particles and role in the degradation of platelet-activating factor, J. Biol. Chem. 262 (1987) 4215–4222. S.A. Karabina, M. Elisaf, E. Bairaktari, C. Tzallas, K.C. Siamopoulos, A.D. Tselepis, Increased activity of platelet-activating factor acetylhydrolase in low-density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia, Eur. J. Clin. Investig. 27 (1997) 595–602. C. Dentan, A.D. Tselepis, M.J. Chapman, E. Ninio, Pefabloc, 4-[2aminiethyl]benzensulfonyl fluoride, is a new, potent, nontoxic and irreversible inhibitor of PAF-degrading acethylhydrolase, Biochim. Biophys. Acta 1299 (1996) 353–357. S. Benitez, J.L. Sanchez-Quesada, V. Ribas, O. Jorba, F. Blanco-Vaca, F. Gonzalez-Sastre, J. Ordonez-Llanos, Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction, Circulation 108 (2003) 92–96. C. Blencowe, A. Hermetter, G.M. Kostner, H.P. Deigner, Enhanced association of platelet-activating factor acetylhydrolase with lipoprotein (a) in comparison with low density lipoprotein, J. Biol. Chem. 270 (1995) 31151–31157. S.A. Karabina, M.C. Elisaf, J. Goudevenos, K.C. Siamopoulos, D. Sideris, A.D. Tselepis, PAF-acetylhydrolase activity of Lp(a) before and during Cu(2+)induced oxidative modification in vitro, Atherosclerosis 125 (1996) 121–134. A.D. Tselepis, S.-A. Karabina, D. Stengel, R. Piédagnel, M.J. Chapman, E. Ninio, N-linked glycosylation of macrophage-derived PAF-AH is a major determinant of enzyme association with plasma HDL, J. Lipid Res. 42 (2002) 1645–1654. A.D. Tselepis, C. Dentan, S.A. Karabina, M.J. Chapman, E. Ninio, PAFdegrading acetylhydrolase is preferentially associated with dense LDL and VHDL-1 in human plasma. Catalytic characteristics and relation to the monocyte-derived enzyme, Arterioscler. Thromb. Vasc. Biol. 15 (1995) 1764–1773. G.K. Marathe, G.A. Zimmerman, T.M. McIntyre, PAF-acetylhydrolase,
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
and not Paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles, J. Biol. Chem. 278 (2003) 3937–3947. D.M. Stafforini, K. Satoh, D.L. Atkinson, L.W. Tjoelker, C. Eberhardt, H. Yoshida, T. Imaizumi, S. Takamatsu, G.A. Zimmerman, T.M. McIntyre, P.W. Gray, S.M. Prescott, Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase, J. Clin. Invest. 97 (1996) 2784–2791. L. Rodrigo, B. Mackness, P.N. Durrington, A. Hernandez, M.I. Mackness, Hydrolysis of platelet-activating factor by human serum paraoxonase, Biochem. J. 354 (2001) 1–7. M. Liu, P.V. Subbaiah, Hydrolysis and transesterification of plateletactivating factor by lecithin-cholesterol acyltransferase, Proc. Natl. Acad. Sci. U. S. A. 91 (1994) 6035–6039. J. Goyal, K. Wang, M. Liu, P.V. Subbaiah, Novel function of lecithincholesterol acyltransferase. Hydrolysis of oxidized polar phospholipids generated during lipoprotein oxidation, J. Biol. Chem. 272 (1997) 16231–16239. M.A. Gijon, C. Perez, E. Mendez, M. Sanchez Crespo, Phospholipase A2 from plasma of patients with septic shock is associated with high-density lipoproteins and C3 anaphylatoxin: some implications for its functional role, Biochem. J. 306 (Pt 1) (1995) 167–175. C. Dentan, P. Lesnik, M.J. Chapman, E. Ninio, Paf-acether-degrading acetylhydrolase in plasma LDL is inactivated by copper- and cellmediated oxidation, Arterioscler. Thromb. 14 (1994) 353–360. G. Ambrosio, A. Oriente, C. Napoli, G. Palumbo, P. Chiariello, G. Marone, M. Condorelli, M. Chiariello, M. Triggiani, Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor, J. Clin. Invest. 93 (1994) 2408–2416. D.C. Tsoukatos, M. Arborati, T. Liapikos, K.L. Clay, R.C. Murphy, M.J. Chapman, E. Ninio, Copper-catalyzed oxidation mediates PAF formation in human LDL subspecies. Protective role of PAF:acetylhydrolase in dense LDL, Arterioscler. Thromb. Vasc. Biol. 17 (1997) 3505–3512. V.N. Bochkov, A. Kadl, J. Huber, F. Gruber, B.R. Binder, N. Leitinger, Protective role of phospholipid oxidation products in endotoxin-induced tissue damage, Nature 419 (2002) 77–81. L.W. Tjoelker, C. Eberhardt, J. Unger, H. Le Trong, G.A. Zimmerman, T.M. McIntyre, D.M. Stafforini, S.M. Prescott, P.W. Gray, Plasma plateletactivating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad, J. Biol. Chem. 43 (1995) 25481–25487. Y. Cao, D.M. Stafforini, G.A. Zimmerman, T.M. McIntyre, S.M. Prescott, Expression of plasma platelet-activating factor acetylhydrolase is transcriptionally regulated by mediators of inflammation, J. Biol. Chem. 273 (1998) 4012–4020. C. Sumita, M. Maeda, Y. Fujio, J. Kim, J. Fujitsu, S. Kasayama, I. Yamamoto, J. Azuma, Pioglitazone induces plasma platelet activating factor-acetylhydrolase and inhibits platelet activating factor-mediated cytoskeletal reorganization in macrophage, Biochim. Biophys. Acta 1673 (2004) 115–121. J.H. Min, M.K. Jain, C. Wilder, L. Paul, R. ApitzCastro, D.C. Aspleaf, M.H. Gelb, Membrane-bound plasma platelet activating factor acetylhydrolase acts on substrate in the aqueous phase, Biochem. USA 38 (1999) 12935–12942. M.L. Wardlow, C.P. Cox, K.E. Meng, D.E. Greene, R.S. Farr, Substrate specificity and partial characterization of the paf-acylhydrolase in human serum that rapidly inactivates platelet-activating factor, J. Immunol. 136 (1986) 3441–3446. G. Subbanagounder, N. Leitinger, D.C. Schwenke, J.W. Wong, H. Lee, C. Rizza, A.D. Watson, K.F. Faull, A.M. Fogelman, J.A. Berliner, Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position, Arterioscler. Thromb. Vasc. Biol. 20 (2000) 2248–2254. K.E. Stremler, D.M. Stafforini, S.M. Prescott, G.A. Zimmerman, T.M. McIntyre, An oxidized derivative of phosphatidylcholine is a substrate for the platelet-activating factor acetylhydrolase from human plasma, J. Biol. Chem. 264 (1989) 5331–5334. D.M. Stafforini, J.R. Sheller, T.S. Blackwell, A. Sapirstein, F.E. Yull, T.M. McIntyre, J.V. Bonventre, S.M. Prescott, L.J. Roberts II, Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases, J. Biol. Chem. 281 (2006) 4616–4623.
1357
[44] L.W. Tjoelker, C. Wilder, C. Eberhardt, D.M. Stafforini, G. Dietsch, B. Schimpf, S. Hooper, H. Letrong, L.S. Cousens, G.A. Zimmerman, Y. Yamada, T.M. McIntyre, S.M. Prescott, P.W. Gray, Anti-inflammatory properties of a platelet-activating factor acetylhydrolase, Nature 374 (1995) 549–553. [45] E.N. Morgan, E.M. Boyle, W. Yun, J.C. Kovacich, T.G. Canty, E. Chi, T.H. Pohlman, E.D. Verrier, Platelet-activating factor acetylhydrolase prevents myocardial ischemia–reperfusion injury, Circulation 100 (1999) 365–368. [46] M.S. Caplan, M. Lickerman, L. Adler, G.N. Dietsch, A. Yu, The role of recombinant platelet-activating factor acetylhydrolase in a neonatal rat model of necrotizing enterocolitis, Pediatr. Res. 42 (1997) 779–783. [47] W.R. Henderson Jr., J. Lu, K.M. Poole, G.N. Dietsch, E.Y. Chi, Recombinant human platelet-activating factor-acetylhydrolase inhibits airway inflammation and hyperreactivity in mouse asthma model, J. Immunol. 164 (2000) 3360–3367. [48] G. Theilmeier, B. De Geest, P.P. Van Veldhoven, D. Stengel, C. Michiels, M. Lox, M. Landeloos, M.J. Chapman, E. Ninio, D. Collen, B. Himpens, P. Holvoet, HDL-associated PAF-AH reduces endothelial adhesiveness in apoE−/− mice, FASEB J. 14 (2000) 2032–2039. [49] R. Quarck, B. De Geest, D. Stengel, A. Mertens, M. Lox, G. Theilmeier, C. Michiels, M. Raes, H. Bult, D. Collen, P. Van Veldhoven, E. Ninio, P. Holvoet, Adenovirus-mediated gene transfer of human platelet-activatingfactor- acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice, Circulation 103 (2001) 2495–2500. [50] H. Noto, M. Hara, K. Karasawa, O.N. Iso, H. Satoh, M. Togo, Y. Hashimoto, Y. Yamada, T. Kosaka, M. Kawamura, S. Kimura, K. Tsukamoto, Human plasma platelet-activating factor acetylhydrolase binds to all the murine lipoproteins, conferring protection against oxidative stress, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 829–835. [51] P. Turunen, J. Jalkanen, T. Heikura, H. Puhakka, J. Karppi, K. Nyyssonen, S. Yla-Herttuala, Adenovirus-mediated gene transfer of Lp-PLA2 reduces LDL degradation and foam cell formation in vitro, J. Lipid Res. 45 (2004) 1633–1639. [52] H. Arakawa, J.Y. Qian, D. Baatar, K. Karasawa, Y. Asada, Y. Sasaguri, E.R. Miller, J.L. Witztum, H. Ueno, Local expression of platelet-activating factor-acetylhydrolase reduces accumulation of oxidized lipoproteins and inhibits inflammation, shear stress-induced thrombosis, and neointima formation in balloon-injured carotid arteries in nonhyperlipidemic rabbits, Circulation 111 (2005) 3302–3309. [53] U. Singh, S. Zhong, M. Xiong, T.B. Li, A. Sniderman, B.B. Teng, Increased plasma non-esterified fatty acids and platelet-activating factor acetylhydrolase are associated with susceptibility to atherosclerosis in mice, Clin. Sci. (Lond.) 106 (2004) 421–432. [54] E.M. Rubin, R.M. Krauss, E.A. Spangler, J.G. Verstuyft, S.M. Clift, Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI, Nature 353 (1991) 265–267. [55] B. De Geest, D. Stengel, M. Landeloos, M. Lox, L. Le Gat, D. Collen, P. Holvoet, E. Ninio, Effect of overexpression of human apo A-I in C57BL/6 and C57BL/6 apo E-deficient mice on 2 lipoprotein-associated enzymes, platelet-activating factor acetylhydrolase and paraoxonase: comparison of adenovirus-mediated human apo A-I gene transfer and human apo A-I transgenesis, Arterioscler. Thromb. Vasc. Biol. 20 (2000) E68–E75. [56] E. Boisfer, D. Stengel, D. Pastier, P.M. Laplaud, N. Dousset, E. Ninio, A.D. Kalopissis, Antioxidant properties of HDL in transgenic mice overexpressing human apolipoprotein A-II, J. Lipid Res. 43 (2002) 732–741. [57] P. Holvoet, K. Peeters, S. Lund-Katz, A. Mertens, P. Verhamme, R. Quarck, D. Stengel, M. Lox, E. Deridder, H. Bernar, M. Nickel, G. Theilmeier, E. Ninio, M.C. Phillips, Arg123–Tyr166 domain of human ApoA-I is critical for HDL-mediated inhibition of macrophage homing and early atherosclerosis in mice, Arterioscler. Thromb. Vasc. Biol. 21 (2001) 1977–1983. [58] T.M. Forte, M.N. Oda, L. Knoff, B. Frei, J. Suh, J.A. Harmony, W.D. Stuart, E.M. Rubin, D.S. Ng, Targeted disruption of the murine lecithin: cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration, J. Lipid Res. 40 (1999) 1276–1283. [59] V. Angeli, J. Llodra, J.X. Rong, K. Satoh, S. Ishii, T. Shimizu, E.A. Fisher, G.J. Randolph, Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization, Immunity 21 (2004) 561–574.
1358
S.-A. Karabina, E. Ninio / Biochimica et Biophysica Acta 1761 (2006) 1351–1358
[60] J.A. Blackie, J.C. Bloomer, M.J. Brown, H.Y. Cheng, B. Hammond, D.M. Hickey, R.J. Ife, C.A. Leach, V.A. Lewis, C.H. Macphee, K.J. Milliner, K.E. Moores, I.L. Pinto, S.A. Smith, I.G. Stansfield, S.J. Stanway, M.A. Taylor, C.J. Theobald, The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2, Bioorg. Med. Chem. Lett. 13 (2003) 1067–1070. [61] M. Miwa, T. Miyake, T. Yamanaka, J. Sugatani, Y. Suzuki, S. Sakata, Y. Araki, M. Matsumoto, Characterization of serum platelet-activating factor (PAF) acetylhydrolase: correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children, J. Clin. Invest. 82 (1983) 1983–1991. [62] L.M. Kuitert, K.P. Hui, S. Uthayarkumar, W. Burke, A.C. Newland, S. Uden, N.C. Barnes, Effect of the platelet-activating factor antagonist UK74,505 on the early and late response to allergen, Am. Rev. Respir. Dis. 147 (1993) 82–86. [63] A. Freitag, R.M. Watson, G. Matsos, C. Eastwood, P.M. O'Byrne, Effect of a platelet activating factor antagonist, WEB 2086, on allergen induced asthmatic responses, Thorax 48 (1993) 594–598. [64] D.J. Evans, P.J. Barnes, M. Cluzel, B.J. O'Connor, Effects of a potent platelet-activating factor antagonist, SR27417A, on allergen-induced asthmatic responses, Am. J. Respir. Crit. Care Med. 156 (1997) 11–16. [65] N.R. Henig, M.L. Aitken, M.C. Liu, A.S. Yu, W.R. Henderson Jr., Effect of recombinant human platelet-activating factor-acetylhydrolase on allergeninduced asthmatic responses, Am. J. Respir. Crit. Care Med. 162 (2000) 523–527. [66] D.P. Schuster, M. Metzler, S. Opal, S. Lowry, R. Balk, E. Abraham, H. Levy, G. Slotman, E. Coyne, S. Souza, J. Pribble, Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: phase IIb, multicenter, randomized, placebocontrolled, clinical trial, Crit. Care Med. 31 (2003) 1612–1619. [67] S. Opal, P.F. Laterre, E. Abraham, B. Francois, X. Wittebole, S. Lowry, J.F. Dhainaut, B. Warren, T. Dugernier, A. Lopez, M. Sanchez, I. Demeyer, L. Jauregui, J.A. Lorente, W. McGee, K. Reinhart, S. Kljucar, S. Souza, J. Pribble, Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial, Crit. Care Med. 32 (2004) 332–341. [68] R.A. Claus, S. Russwurm, B. Dohrn, M. Bauer, W. Losche, Plasma platelet-activating factor acetylhydrolase activity in critically ill patients, Crit. Care Med. 33 (2005) 1416–1419. [69] C. Lee, F. Sigari, T. Segrado, S. Horkko, S. Hama, P.V. Subbaiah, M. Miwa, M. Navab, J.L. Witztum, P.D. Reaven, All ApoB-containing lipoproteins induce monocyte chemotaxis and adhesion when minimally modified. Modulation of lipoprotein bioactivity by platelet-activating factor acetylhydrolase, Arterioscler. Thromb. Vasc. Biol. 19 (1999) 1437–1446. [70] Y. Yamada, S. Ichihara, T. Fujimura, M. Yokota, Identification of the G994/T missence mutation in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men, Metabolism 47 (1998) 177–181. [71] M. Hiramoto, H. Yoshida, T. Imaizumi, N. Yoshimizu, K. Satoh, A mutation in plasma platelet-activating factor acetylhydrolase (Val279(Phe), is a genetic risk factor for stroke, Stroke 28 (1997) 2417–2420. [72] Y. Yamada, H. Izawa, S. Ichihara, F. Takatsu, H. Ishihara, H. Hirayama, T. Sone, M. Tanaka, M. Yokota, Prediction of the risk of myocardial infarction from polymorphisms in candidate genes, N. Engl. J. Med. 347 (2002) 1916–1923. [73] M.J. Caslake, C.J. Packard, Lipoprotein-associated phospholipase A(2) as a biomarker for coronary disease and stroke, Nat. Clin. Pract. Cardiovasc. Med. 2 (2005) 529–535. [74] E. Ninio, Phospholipid mediators in the vessel wall: involvement in atherosclerosis, Curr. Opin. Clin. Nutr. Metab. Care 8 (2005) 123–131. [75] C.J. Packard, D.S. O'Reilly, M.J. Caslake, A.D. McMahon, I. Ford, J. Cooney, C.H. Macphee, K.E. Suckling, M. Krishna, F.E. Wilkinson, A. Rumley, G.D. Lowe, Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group, N. Engl. J. Med. 343 (2000) 1148–1155.
[76] G.J. Blake, N. Dada, J.C. Fox, J.E. Manson, P.M. Ridker, A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women, J. Am. Coll. Cardiol. 38 (2001) 1302–1306. [77] V. Tsimihodimos, S.A. Karabina, A.P. Tambaki, E. Bairaktari, G. Miltiadous, J.A. Goudevenos, M.A. Cariolou, M.J. Chapman, A.D. Tselepis, M. Elisaf, Altered distribution of platelet-activating factor- acetylhydrolase activity between LDL and HDL as a function of the severity of hypercholesterolemia, J. Lipid Res. 43 (2002) 256–263. [78] V. Tsimihodimos, A. Kakafika, A.P. Tambaki, E. Bairaktari, M.J. Chapman, M. Elisaf, A.D. Tselepis, Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apoB-containing lipoproteins, J. Lipid Res. 44 (2003) 927–934. [79] K. Winkler, C. Abletshauser, I. Friedrich, M.M. Hoffmann, H. Wieland, W. Marz, Fluvastatin slow-release lowers platelet-activating factor acetyl hydrolase activity: a placebo-controlled trial in patients with type 2 diabetes, J. Clin. Endocrinol. Metab. 89 (2004) 1153–1159. [80] S. Blankenberg, D. Stengel, H. Rupprecht, C. Bickel, J. Meyer, F. Cambien, L. Tiret, E. Ninio, Plasma PAF-acetylhydrolase in patients with coronary artery disease. Results of a cross-sectional analysis, J. Lipid Res. 44 (2003) 1381–1386. [81] C.M. Ballantyne, R.C. Hoogeveen, H. Bang, J. Coresh, A.R. Folsom, G. Heiss, A.R. Sharrett, Lipoprotein-associated phospholipase A2, highsensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, Circulation 109 (2004) 837–842. [82] S. Kruse, X.-Q. Mao, A. Heinzman, S. Blattmann, M.H. Roberts, S. Braun, P.-S. Gao, J. Forster, J. Kuehr, J.M. Hopkins, T. Shirakawa, K.A. Deichman, The Ile198Thr and Ala379Val variants of plasmatic Paf-acetylhydrolase impair catalytical activities and are associated with atopy and asthma, Am. J. Hum. Genet. 66 (2000) 1522–1530. [83] A.M. Abuzeid, E. Hawe, S.E. Humphries, P.J. Talmud, Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe, Atherosclerosis 168 (2003) 283–288. [84] E. Ninio, D. Tregouet, J.L. Carrier, D. Stengel, C. Bickel, C. Perret, H.J. Rupprecht, F. Cambien, S. Blankenberg, L. Tiret, Platelet-activating factoracetylhydrolase and PAF-receptor gene haplotypes in relation to future cardiovascular event in patients with coronary artery disease, Hum. Mol. Genet. 13 (2004) 1341–1351. [85] P.T. Wootton, J.W. Stephens, S.J. Hurel, H. Durand, J. Cooper, E. Ninio, S.E. Humphries, P.J. Taimud, Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus, Atherosclerosis (in press) (Electronic publication ahead of print). [86] E. Rizos, A.P. Tambaki, I. Gazi, A.D. Tselepis, M. Elisaf, Lipoproteinassociated PAF-acetylhydrolase activity in subjects with the metabolic syndrome, Prostaglandins Leukot. Essent. Fat. Acids 72 (2005) 203–209. [87] C. Iribarren, M.D. Gross, J.A. Darbinian, D.R. Jacobs Jr., S. Sidney, C.M. Loria, Association of lipoprotein-associated phospholipase A2 mass and activity with calcified coronary plaque in young adults: the CARDIA study, Arterioscler. Thromb. Vasc. Biol. 25 (2005) 216–221. [88] D.N. Kiortsis, S. Tsouli, E.S. Lourida, V. Xydis, M.I. Argyropoulou, M. Elisaf, A.D. Tselepis, Lack of association between carotid intimamedia thickness and PAF-acetylhydrolase mass and activity in patients with primary hyperlipidemia, Angiology 56 (2005) 451–458. [89] S. Campo, M.A. Sardo, A. Bitto, A. Bonaiuto, G. Trimarchi, M. Bonaiuto, M. Castaldo, C. Saitta, S. Cristadoro, A. Saitta, Platelet-activating factor acetylhydrolase is not associated with carotid intima-media thickness in hypercholesterolemic Sicilian individuals, Clin. Chem. 50 (2004) 2077–2082. [90] D.C. Tsoukatos, T.A. Liapikos, A.D. Tselepis, M.J. Chapman, E. Ninio, Platelet-activating factor acetylhydrolase and transacetylase activities in human plasma low-density lipoprotein, Biochem. J. 357 (2001) 457–464. [91] C.H. Macphee, J. Nelson, A. Zalewski, Role of lipoprotein-associated phospholipase A(2) in atherosclerosis and its potential as a therapeutic target, Curr. Opin. Pharmacol. 6 (2006) 154–161.