Plasma Platelet-activating Factor Acetylhydrolase Activity Research Articles

Clinical significance of plasma PAF acetylhydrolase activity measurements as a biomarker of anaphylaxis: Cross-sectional study.

IntroductionPlatelet-activating factor (PAF) has a direct role as a mediator in the pathogenesis of various disorders with an inflammatory component, including those with allergic aetiology. The peripheral blood concentration of PAF is dynamically regulated by plasma PAF acetylhydrolase (PAF-AH). Previous research suggest that low activity of plasma PAF-AH could be a predictive marker for increased severity of some types of allergic hypersensitivity reactions–especially anaphylaxis. The purpose of the study was to evaluate the association between plasma PAF-AH activity and severity in patients with anaphylactic reactions following a wasp or bee sting.Materials and methodsThe study group of 89 patients was divided into two subgroups depending on the increasing severity of the most severe anaphylactic reaction in the past, which was assessed according to the Müller’s scale. The first subgroup included participants with a history of hypersensitivity reactions up to grade II. The second subgroup consisted of patients who have experienced at least one grade III or IV reactions in the past. A control group of 20 people was established. Plasma PAF-AH activity was measured using a colorimetric method.ResultsIt has been observed that plasma activity of platelet-activating factor acetylhydrolase was significantly lower in patients with anaphylaxis history compared to the control group with negative atopic history (on average 21.38 nmol/min/ml for the control group, 9.47 nmol/min/ml for the first subgroup and 10.16 nmol/min/ml for the second subgroup, in both cases p < 0.0001).ConclusionThe plasma activity of PAF-AH is a promising parameter that can help to distinguish a group of patients not threatened with development of anaphylaxis and not requiring laborious or expensive prophylactic procedures.

Evaluation of maternal plasma platelet activating factor acetylhydrolase activity and mRNA expression in pre-eclampsia: a case control study

Preeclampsia (PE) remains a leading cause of maternal morbidity and mortality all over the world. However, its aetiology and pathophysiology remain elusive. Platelet activating factor (PAF) is produced in response to oxidative stress and is a potent hypotensive agent. PAF acetylhydrolase (PAF-AH) inactivates PAF and is seen to decrease in normotensive women. The role of PAF-AH in preeclampsia has been in investigational literature, so far. The few studies done have shown a positive association of elevated levels of PAF-AH with preeclampsia. However, this marker has not been studied in the Indian population to-date and such studies are needed to elucidate the pathogenesis of this condition. Our study aimed to determine the PAF-AH activity by spectrophotometric assay in maternal plasma of 73 PE patients versus 73 normotensive controls and plasma PAF-AH mRNA expression to know the aberration of PAF-AH activity at the genetic level. Relative mRNA expression was calculated by Δ DCT method and a fold change was calculated by 2–ΔDCT. We found that the mean plasma PAF-AH activity levels among cases was significantly higher than the normotensive controls. However, the mRNA expression of the PAF-AH gene was similar between the cases and controls, as well as between severe and non-severe preeclampsia (true fold change =1). To conclude, PAF-AH appears to be increased in women with preeclampsia and hence may contribute to pathophysiology and severity. However, a larger sample size will be required to reiterate this association. Recently, PAF-AH inhibitors such as Darapladib has been tested as a therapeutic option in atherosclerosis. After studying the role of PAF-AH in the pathogenesis of PE, PAF-AH inhibitors may be used as a therapeutic tool in the future in PE. IMPACT STATEMENT What is already known on this subject? Platelet activating factor (PAF) is produced in response to oxidative stress and is a potent hypotensive agent. PAF acetylhydrolase (PAF-AH) hydrolyses and inactivates PAF and is seen to decrease in normotensive women. The role of platelet activating factor-acetylhydrolase (PAF-AH) in preeclampsia has been investigational so far. Few studies done have shown a positive association of elevated levels of PAF-AH in preeclamptic women. What do the results of this study add? Our study aimed to determine the activity of PAF-AH in maternal plasma of PE patients versus normal pregnancy and plasma PAF-AH mRNA expression to know the aberration of PAF-AH activity at the level of the gene. We found that plasma PAF-AH activity among preeclamptics was significantly higher than in the controls with a possible role in early-onset preeclampsia (<32 weeks), in the Indian population. This marker has never been studied in this population earlier. The results of our study re-emphasised its role in the pathogenesis of preeclampsia. What are the implications of these findings for clinical practice and/or further research? Such studies are important to not only give us a greater understanding of the various pathways involved in this multifactorial dreaded condition, but can also offer us a marker for early identification of women at risk. Recently, PAF-AH inhibitors like Darapladib has been tested as a therapeutic option in atherosclerosis. After studying the role of PAF-AH in the pathogenesis of PE, PAF-AH inhibitors may be used as a therapeutic tool in the future in PE.

Sesame lignans reduce LDL oxidative susceptibility by downregulating the platelet-activating factor acetylhydrolase.

Low-density lipoprotein (LDL) oxidative susceptibility is recognized as a risk factor for atherosclerosis. We previously reported that the ingestion of a supplement containing sesame lignans (sesamin/episesamin) for 4 weeks reduced LDL oxidative susceptibility in humans. To elucidate the mechanisms underlying this observation, 12-week-old New Zealand White rabbits were fed a fat/cholesterol-enriched diet (100 g/day) for 6 weeks followed by oral administration of vehicle (control) or sesame lignans (50 mg/kg) for 4 weeks with the fat/cholesterol-enriched diet. The results showed that the ingestion of sesame lignans prolonged LDL oxidation lag time, regardless of the existence of the anti-oxidative catechol metabolite of sesamin/episesamin in LDL. Plasma platelet-activating factor acetylhydrolase (PAF-AH) activity was significantly reduced by sesame lignans. The prolongation of LDL oxidation lag time was abolished by the addition of a PAF-AH inhibitor. The expression level of pro-inflammatory cytokines and macrophage infiltration observed in the liver following the feeding of the fat/cholesterol-enriched diet were also significantly reduced by sesame lignans. These results indicate that sesame lignans reduce LDL oxidative susceptibility by downregulating plasma PAF-AH activity via the reduction of inflammation in the liver induced by fat/cholesterol-enriched diets.

The effect of exenatide (a GLP-1 analog) and sitagliptin (a DPP-4 inhibitor) on plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and concentration in normal and fructose-fed rats

Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats.Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 µg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA.The four-week exenatide (5 µg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P < 0.001) and decreased the level of circulating oxLDL (-42%, P < 0.05) and MCP-1 (-23%, P < 0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P < 0.001) and apoB/apoA-I ratio (-75%, P < 0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction.Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity.

Effects of apoC1 genotypes on the hormonal levels, metabolic profile and PAF-AH activity in Chinese women with polycystic ovary syndrome

BackgroundElevated serum levels of apolipoprotein (apo) C1 may be an early protein marker of metabolic abnormality in women with polycystic ovary syndrome (PCOS). It is not clear, however, whether there are any relationships between the apoC1 rs4420638A/G and -317deletion (H1)/insertion (H2) polymorphisms and PCOS. We investigated the relationship between these two variants and the risk of PCOS, evaluated the genotypic effects on clinical, hormonal and metabolic indexes and plasma platelet-activating factor acetylhydrolase (PAF-AH) activity, and defined the association of apoC1 gene variants with apoE ε2/ε3/ε4 polymorphisms.MethodsThis is a cross-sectional study of 877 women with PCOS and 761 controls. The apoC1 rs4420638A/G genotype was determined by a Taqman real-time PCR allelic discrimination assay. The apoC1–317H1/H2 and apoE ε2/ε3/ε4 genotypes were measured using PCR and restriction fragment length polymorphism analysis. The clinical, hormonal and metabolic parameters and PAF-AH activity were measured.ResultsThe frequencies of apoC1 rs4420638A/G and -317H1/H2 genotypes and alleles were similar between PCOS and control groups (P > 0.05). However, the rs4420638 G allele was related to increased serum luteinizing hormone, cholesterol and apoB levels, and the ratio of apoB to apoA1 (P < 0.05), and the -317H1H1 genotype was associated with a higher acne grade score and a higher ratio of apoB-PAF-AH to H-PAF-AH activity (P < 0.05) in patients with PCOS. We also demonstrated that the apoC1 rs4420638A/G and -317H1/H2 gene variants existed in moderate to reasonably high linkage disequilibrium with apoE ε2/ε3/ε4 polymorphisms in Chinese women.ConclusionThe apoC1 rs4420638A/G and -317H1/H2 gene variants might be involved in endocrine abnormalities of reproductive axis, metabolic abnormalities and chronic inflammation in PCOS, although no association was observed between the apoC1 genetic variants and the risk of PCOS in Chinese women.

“Association between platelet activating factor acetylhydrolase and diabetic retinopathy: Does inflammation affect the retinal status?”

AimTo assess the role of plasma platelet activating factor acetylhydrolase (PAF-AH) in pathogenesis and progression of diabetic retinopathy (DR). Materials and methodsSixty eight diabetics and 23 age-frequency-matched non-diabetic patients underwent blood sampling and the plasma PAF-AH activity was calculated. The diabetic patients were further classified into two groups, according to the Early Treatment Diabetic Retinopathy Study (ETDRS) classification, based on indirect fundoscopy and fluorescein angiography. Thirty seven patients with non-proliferative DR (NPDR) and 31 patients with proliferative DR (PDR) were finally included in the study. ResultsThe plasma PAF-AH activity was increased in diabetic patients with PDR (0.206μmol/min/ml) compared to control group (0.114μmol/min/ml, post-hoc Bonferroni comparison test: p<0.0001) and to NPDR group (0.147μmol/min/ml, post-hoc Bonferroni comparison test: p=0.012). ConclusionsThe activity of PAF-AH in the plasma increases in parallel with DR severity.

Relationship between platelet activating factor acetylhydrolase activity and apolipoprotein B levels in patients with peanut allergy.

BackgroundPlatelet-activating factor (PAF) is a highly potent phospholipid mediator responsible for the life-threatening manifestations of anaphylaxis. PAF acetylhydrolase (PAF-AH) inactivates PAF and protects against severe anaphylaxis whereas deficiency of PAF-AH predisposes to severe or fatal anaphylaxis. Determinants of PAF-AH activity have not been studied in patients with peanut allergy.ObjectivesTo determine whether plasma PAF-AH activity in patients with peanut allergy is related to formation of circulating complexes with apolipoprotein B (apoB) the main surface protein on low density lipoprotein particles.MethodsPlasma PAF-AH activity and apoB concentrations were measured in 63 peanut allergic patients (35 boys, 28 girls, ages 2 – 19 years). ApoB concentration was measured immunoturbidimetrically using goat anti-human apoB. The correlation between PAF-AH activity and apoB concentration was determined.ResultsA positive correlation was found between PAF-AH activity and apoB concentration (r2 = 0.59, P < 0.0001).ConclusionIn peanut allergic patients, PAF-AH activity strongly correlates with apoB concentration, suggesting the presence of circulating PAF-AH- lipoprotein complexes.

Lipoxin A4 and Platelet Activating Factor Are Involved in E. coli or LPS-Induced Lung Inflammation in CFTR-Deficient Mice

CFTR (cystic fibrosis transmembrane conductance regulator) is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del) or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2) or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage) during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1) or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF) levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase) inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.

Maternal and fetal plasma platelet-activating factor acetylhydrolase activity and distribution in pre-eclampsia

Distribution of platelet-activating factor acetylhydrolase (PAF-AH) in lipoproteins plays important roles in the onset of inflammation and atherosclerosis. We hypothesized that women with pre-eclampsia (PE), showing signs of inflammation and oxidative stress, and their fetuses have aberrations of PAF-AH activity and distribution. Maternal and fetal plasma PAF-AH activity, high-density lipoprotein (HDL)-associated PAF-AH (H-PAF-AH) and low-density lipoprotein (LDL)-associated PAF-AH (L-PAF-AH) were examined in women with PE (n = 127) and in women with uncomplicated pregnancies (n = 88). The neonates of women with severe PE (n = 42) had significantly higher plasma PAF-AH, L-PAF-AH activities, and ratio of L-PAF-AH to H-PAF-AH activities than the neonates of women with normal pregnancies (n = 83). The mothers with severe PE (n = 106) and their neonates presented a significantly higher atherogenic index (AI) and triglyceride (TG)/HDL cholesterol (C) ratio than the control mothers and their neonates. The ratio of L-PAF-AH to H-PAF-AH activities correlated positively with TG levels, TG/HDL(C) ratio, and AI and negatively with HDL(C) levels in the neonates of women with PE. The neonates of women with severe PE presented with a chronic inflammation status, increased oxidative stress, and unfavorable lipid changes, which may potentially link to related complications responsible for oxidative stress and inflammation in later life.

Plasma Platelet-Activating Factor–Acetyl Hydrolase Activity and the Levels of Free Forms of Biomarker of Lipid Peroxidation in Cerebrospinal Fluid of Patients With Aneurysmal Subarachnoid Hemorrhage

Free radicals and lipid peroxidation are thought to be related to the vasospasm generation after subarachnoid hemorrhage (SAH). Plasma platelet-activating factor-acetyl hydrolase (PAF-AH) degrades phospholipids with an oxidatively modified fatty acyl chain. To compare plasma PAF-AH activity and free forms of biomarker of lipid peroxidation in cerebrospinal fluid (CSF) between patients with and without symptomatic vasospasm (SVS) after SAH. The identification of PAF-AH in CSF was performed by Western blotting. The genotype at position 279 of the plasma PAF-AH gene was determined. The activities of PAF-AH and the levels of free 8-iso-prostaglandin F2α (free isoPs), free hydroxyoctadecadienoic acid (free HODE), and free hydroxyeicosatetraenoic acid (free HETE) in CSF were measured. The PAF-AH in CSF was confirmed to be only the plasma type. The genotype of the plasma PAF-AH was not different between patients with and without SVS. Free isoPs, free HODE, and free HETE showed higher values in patients without SVS in 0 to 4 days and 5 to 9 days after SAH. The PAF-AH activity also was higher in patients without SVS in 0 to 4 days and 5 to 9 days after SAH. The associations between PAF-AH activity and free isoPs, and between PAF-AH activity and free HODE were significant. Oxidized lipids of lipoproteins and blood cell membranes produced by reactive oxygen species in CSF when SAH occurs may be the main source of lipid peroxidation. Plasma PAF-AH can hydrolyze oxidized phospholipids, and may attenuate the spreading of lipid peroxidation and participate in defense mechanisms against vasospasm after SAH.

Serum platelet-activating factor acetylhydrolase activity: relationship with metabolic syndrome in women with history of gestational diabetes mellitus

Objective. The aim of this study was to evaluate plasma platelet-activating factor acetylhydrolase (PAF-AH) activity in euglycaemic women with history of gestational diabetes (GDM), and to explore whether this activity is associated with metabolic syndrome (MS) in this group of women.Methods. The cross-sectional study included 36 women with history of GDM and 40 women with history of normal glucose tolerance in pregnancy (control group).Results. Compared to the controls, the GDM group had significantly higher mean values for serum glucose, insulin, HOMA-IR, triglyceride, GGT and plasma PAF-AH activity, and a statistically higher prevalence of MS. Within the GDM group, women diagnosed with MS had significantly higher PAF-AH activity than those without MS (p = 0.002).Conclusion. This is the first study to have shown that plasma PAF-AH activity and GGT levels may be significant for evaluating atherosclerosis risk and metabolic hepatic damage in women with history of GDM.

Activity and distribution of plasma platelet-activating factor acetylhydrolase in polycystic ovary syndrome patients with insulin resistance

To investigate the relationship between activity of plasma platelet-activating factor acetylhydrolase (PAF-AH) and insulin resistance (IR) in patients with polycystic ovary syndrome (PCOS). From Oct. 2006 to Jan. 2008, 105 PCOS patients undergoing treatment in Department of Obstetrics and Gynecology of Second Hospital affiliated to West China University were enrolled in the study, among 53 cases with homeostatic model assessment IR (HOMA-IR) exceed or equal 2.77 as IR-PCOS group and 52 cases with HOMA-IR less than 2.77 as non IR-PCOS group. In the mean time, 53 infertile women due to fallopian tube or husband factors were chosen as control group. Plasma PAF-AH activity, high-density lipoprotein-associated PAF-AH (H-PAF-AH) activity, low-density lipoprotein-associated PAF-AH (L-PAF-AH) activity, the ratio of L-PAF-AH to H-PAF-AH activity were measured and compared among three groups. The method of Pearson correlation analysis and stepwise multiple regression analysis were used to study the relationship between the ratio of L-PAF-AH to H-PAF-AH activities and hormonal and metabolic parameters. (1) Plasma PAF-AH activity [(0.055 ± 0.012) mmol x L(-1) x min(-1)], L-PAF-AH activity [(0.052 ± 0.012) mmol x L(-1) x min(-1)], and the ratio of L-PAF-AH to H-PAF-AH activity (23 ± 6) in the IR-PCOS group were significantly higher than those at control group [(0.050 ± 0.009) mmol x L(-1) x min(-1), (0.047 ± 0.009) mmol x L(-1) x min(-1) and (18 ± 4)] and non-IR-PCOS group [(0.050 ± 0.0012) mmol x L(-1) x min(-1), (0.048 ± 0.012) mmol x L(-1) x min(-1) and (18 ± 5), P < 0.05]. The ratio of L-PAF-AH to H-PAF-AH activities at IR-PCOS group was also significantly higher than those at Non IR-PCOS and control group after correction for body mass index (P < 0.01). (2) Pearson correlation analysis showed that the ratio of L-PAF-AH to H-PAF-AH in PCOS patients was positively correlated with atherogenic index, age, body mass index, waist-to-hip ratio, HOMA-IR, triglyceride levels, fasting insulin levels, fasting glucose levels, low density lipoprotein cholesterol and total cholesterol (r = 0.644, 0.247, 0.296, 0.212, 0.356, 0.587, 0.377, 0.375, 0.292 and 0.199, respectively, P < 0.05), and negatively correlated with high density lipoprotein cholesterol (r = -0.510, P < 0.05). The multiple stepwise regression analysis showed that atherogenic index and triglyceride were significant variables for the ratio of L-PAF-AH to H-PAF-AH activity (standardized coefficient, beta = 0.515 and 0.201, respectively, P < 0.05). The elevated L-PAF-AH activity may be associated with IR in PCOS patients, and the increased ratio of L-PAF-AH to H-PAF-AH activities may be a potential marker of inflammation in the patients.

In vivo anti-atherogenic properties of cultured gilthead sea bream (Sparus aurata) polar lipid extracts in hypercholesterolaemic rabbits

Abstract The aim of this study was to investigate whether the fish lipid extracts have in vivo anti-atherogenic properties in hypercholesterolaemic rabbits. Fish oil extracts were obtained from cultured gilthead sea bream ( Sparus aurata ) and, for the in vivo experiment, 12 healthy male New Zealand rabbits of specific weight and age were used, which were randomly divided into two groups of six animals each and were given specific diets for 45 days. Group A was given an atherogenic diet, while group B was given an atherogenic diet enriched with Gilthead Sea Bream Polar Lipids (GSBPL). The levels of total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triacylglycerols (TAG) increased in animals of both groups. TC, LDL-C and TAG levels did not exhibit statistical significant differences between groups A and B by day 45, while HDL-C levels increased significantly in group B in comparison with group A by day 45. Plasma PAF-acetylhydrolase (PAF-AH) activity increased significantly in group B at the end of the experiment, in comparison with group A, while platelet aggregation efficiency was reduced in group B rabbits. Rabbits of group B (atherogenic diet supplemented with GSBPL) developed early atherosclerosis lesions, of statistically significantly lower degree ( p = 0.017) than did group A.

Increased PAFAH and Oxidized Lipids Are Associated With Inflammation and Atherosclerosis in Hypercholesterolemic Pigs

To study the association of PAF-acetyl hydrolase (PAFAH) activity with inflammation, oxidative stress, and atherosclerosis in hypercholesterolemic swine. Cholesterol-rich diet feeding of miniature pigs was associated with an increase in PAFAH activity and an increase of the PAFAH to PON1 ratio. PLA2G7 RNA (coding for PAFAH) expression was increased in blood monocytes and plaque macrophages. Increased PAFAH activity was associated with higher plasma lysophosphatidylcholine and correlated with oxidized LDL. In THP1 monocytes and macrophages and in human blood-derived macrophages, oxidized LDL induced PLA2G7 RNA expression. Atherogenic diet feeding induced the accumulation of macrophages and oxidized LDL in the arterial wall leading to atherosclerosis. PAFAH activity correlated positively with plaque size and TNFalpha expression in plaque macrophages. We demonstrated that an increase in PAFAH activity was associated with increased levels of lysophosphatidylcholine, oxidized LDL, and inflammation, resulting in accelerated atherosclerosis in hypercholesterolemic minipigs. The significant correlation between PLA2G7 RNA expression in plaque macrophages and plasma PAFAH activity suggests that the latter is a consequence, rather than a cause of macrophage accumulation. Our cell experiments suggest that oxidized LDL can induce PAFAH, resulting in accumulation of lysophosphatidylcholine that increases the inflammatory action of oxidized LDL.

Altered distribution of plasma platelet-activating factor acetylhydrolase between high-density lipoprotein and low-density lipoprotein in patients with polycystic ovary syndrome

To investigate the association of plasma platelet-activating factor (PAF) acetylhydrolase, high-density lipoprotein-associated PAF acetylhydrolase, and low-density lipoprotein-associated PAF acetylhydrolase activities with metabolic features in patients with polycystic ovary syndrome (PCOS) in Han Chinese women, 141 patients with PCOS and 140 healthy controls were recruited in this case-control study. The results of our study showed that the presence of the changed plasma PAF acetylhydrolase activity and distribution in women with PCOS could contribute to the low-grade chronic inflammation and increased risk of atherosclerosis in these patients.

Abstract: 1467 CONCEPT OF APOLIPOPROTEIN-DEFINED PLASMA LIPOPROTEINS

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

Plasma PAF-acetylhydrolase activity, inflammatory markers and susceptibility of LDL to in vitro oxidation in patients with type 1 diabetes mellitus

Aims We evaluated if type 1 diabetic patients have altered levels of low-grade inflammatory markers including platelet-activating factor acetylhydrolase (PAF-AH) activity, high-sensitivity C-reactive protein (hs-CRP), white blood cells count (WBC), erythrocyte sedimentation rate (ESR) and LDL-cholesterol oxidation coefficient (OxC), and whether their levels are related to clinical complications and the metabolic profile. Methods We studied cross-sectionally 118 outpatients with type 1 diabetes both with ( n = 38) and without ( n = 80) clinical chronic complications, and 110 controls subjects. Results Diabetic patients had higher levels of PAF-AH activity ( p = 0.02), hs-CRP ( p = 0.001), WBC ( p = 0.004) and ESR ( p = 0.0001) than controls. Patients with type 1 diabetes had earlier OxC than the non-diabetic subjects at 1 and 3 h ( p = 0.01) after the addition of CuSO 4. No difference was noted between patients with and without chronic complications. In the patients, correlations were found between PAF-AH activity and OxC at 1 and 3 h. Conclusions It was concluded that the susceptibility of LDL to in vitro oxidation and low-grade inflammation are increased in patients with type 1 diabetes and related to each other. The presence of these markers is probably independent of the presence of chronic clinical complications and reveals the development of early pro-inflammatory state.

Platelet-Activating Factor Involvement in Thioacetamide-Induced Experimental Liver Fibrosis and Cirrhosis

Platelet-activating factor (PAF) is a potent lipid inflammatory mediator acting on cells through its specific receptor. Plasma PAF-acetylhydrolase (PAF-AH) is the main enzyme that inactivates PAF in blood, participating in its homeostasis. The objective of this study was to investigate the involvement of PAF in the liver fibrotic process using an experimental animal model. Liver fibrosis was induced in adult male Wistar rats by administration of thioacetamide (TAA) in drinking water (300 mg/l) for three months. The animals were sacrificed at time 0 (control group) and after 1, 2, and 3 months. PAF levels in liver and blood and PAF-AH activity in plasma were determined. Liver histopathological examination was also performed. TAA administration resulted in progressively increased liver fibrosis, leading finally to the formation of cirrhotic nodules in the liver. Throughout the experiment PAF levels in liver tissue remained stable. "Total" ("free" plus "bound") PAF levels in blood decreased, reaching statistically significant differences in the first and third months compared with the control group (P < 0.05). "Free" PAF levels in blood were higher at one month (P < 0.05) and decreased gradually thereafter. In all treated groups, "bound" PAF levels in blood decreased whereas plasma PAF-AH activity increased (P < 0.05) compared with the control group. Our data indicated alterations of PAF levels in blood and PAF-AH activity during fibrosis induction, implicating participation of PAF in the liver fibrotic process.

Inter-individual variability of plasma PAF-acetylhydrolase activity in ARDS patients andPAFAHgenotype

Platelet activating factor (PAF), a pro-inflammatory phospholipid, stimulates cytokine secretion from polymorphonuclear leukocytes expressing the transmembrane G-protein coupled PAF receptor. Elevated PAF levels are associated with acute respiratory distress syndrome (ARDS) and sepsis severity. The pro-inflammatory effects of PAF are terminated by PAF acetylhydrolase (PAF-AH). We sought to determine whether allelic variants in the human PAFAH gene (Arg92His, Ile198Thr, and Ala379Val) contribute to variability in PAF-AH activity in patient plasma obtained within 72 h of ARDS diagnosis. Plasma PAF-AH activity (mean +/- SD) was higher in patients homozygous for the Arg92 allele compared to His92 allele carriers (2.21 +/- 0.77 vs. 1.64 +/- 0.68 U/min; P < 0.01; n = 31 and 21 respectively). Baseline plasma PAF-AH activity was higher among day 7 survivors vs. day 7 non-survivors (2.05 +/- 0.75 vs. 1.27 +/- 0.63, P = 0.05). These data demonstrate an association between PAF-AH allelic variation, plasma activity, and outcome in ARDS.

Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein

The plasma form of platelet-activating factor (PAF) acetylhydrolase (PAF-AH), also known as lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) inactivates potent lipid messengers such as PAF and modified phospholipids generated in settings of oxidant stress. In humans, PAF-AH circulates in blood in fully active form and associates with high and low density lipoproteins (HDL and LDL). Several studies suggest that the location of PAF-AH affects both the catalytic efficiency and the function of the enzyme in vivo. The distribution of PAF-AH among lipoproteins varies widely among mammals. Here, we report that mouse and human PAF-AHs associate with human HDL particles of different density. We made use of this observation in the development of a binding assay to identify domains required for association of human PAF-AH with human HDL. Sequence comparisons among species combined with domain-swapping and site-directed mutagenesis studies led us to the identification of C-terminal residues necessary for the association of human PAF-AH with human HDL. Interestingly, the region identified is not conserved among PAF-AHs, suggesting that PAF-AH interacts with HDL particles in a manner that is unique to each species. These findings contribute to our understanding of the mechanisms responsible for association of human PAF-AH with HDL and may facilitate future studies aimed at precisely determining the function of PAF-AH in each lipoprotein particle.