Plasma Plasma Platelet-activating Factor Acetylhydrolase Activity Research Articles

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.

“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.

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.

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.

Bovine platelet-activating factor acetylhydrolase (PAF-AH) activity related to fertility

Plasma platelet-activating factor acetylhydrolase (PAF-AH), the enzyme characterized by the association with plasma lipoproteins, degrades platelet-activating factor (PAF) as well as PAF-like oxidatively fragmented phospholipids produced during oxidative stress. Apart from pro-inflammatory properties, PAF is also related to reproductive processes and successful fertility. In order to get a better insight into the involvement of PAF-AH in the fertility of cows, the aim of the study was to determine the PAF-AH activity as well as the C-reactive protein, cholesterol and high density lipoprotein-cholesterol (HDL-C) in the serum of dairy cows throughout the pregnancy and lactation, as well as in infertile cows. The results showed that serum PAF-AH activity changes throughout pregnancy and lactation with a lower level during periparturient period. It is also found higher PAF-AH activity in lactating cows with reproductive disorders compared to high lactating cows without reproductive disorders. Strong correlation between PAF-AH activity and HDL-C concentration indicates that HDL could have considerable influence on PAF-AH activity in bovine plasma. CRP concentration was also lower during transition period suggesting that lactation might stimulate CRP synthesis in bovine. A higher CRP concentration in cows with reproductive disorders compared to fertile cows at the peak of lactation, demonstrates that milk production is not the only factor influencing CRP in cows. A significant correlation between PAF-AH activity and CRP level shows that both parameters could be influenced by reproductive status of dairy cows.

Adenovirus-mediated gene transfer and lipoprotein-mediated protein delivery of plasma PAF-AH ameliorates proteinuria in rat model of glomerulosclerosis

Oxidative stress has been proposed to play a crucial role in glomerulosclerosis, although its in vivo demonstration has proved taxing given the difficulty of inducing gene expression in specific renal cells. In this study, we examined whether the liver-directed expression of plasma platelet-activating factor acetylhydrolase (PAF-AH) would affect the glomerular pathophysiology in Imai rats, an animal model for glomerulosclerosis. Adenovirus-mediated liver-directed gene delivery of human PAF-AH resulted in a significant increase in plasma PAF-AH activity, which was detected almost exclusively on HDL. Histological examination of rats overexpressing PAF-AH showed not only the deposition of PAF-AH in mesangial cells, but also a reduction in hydroxynonenal and matrix protein content in the glomeruli. In situ hybridization analysis was negative for human PAF-AH mRNA in the kidney, while injection of HDL abundant in PAF-AH resulted in the deposition of PAF-AH in mesangial cells. Urine protein levels did not increase in rats overexpressing PAF-AH, while those of control rats increased significantly with age. This study provides direct evidence of the in vivo role of an enzyme that degrades lipid peroxides during the progression of glomerulosclerosis. Adenovirus-mediated extrarenal gene expression and lipoprotein-mediated glomeruli-targeted protein delivery promise to be a novel therapeutic approach to glomerulosclerosis.

A Polymorphism in Plasma Platelet-activating Factor Acetylhydrolase is Involved in Resistance to Immunoglobulin Treatment in Kawasaki Disease

To investigate whether reduced levels of plasma platelet-activating factor acetylhydrolase (PAF-AH) as a result of a genetic polymorphism are involved in the pathogenesis of Kawasaki disease (KD). The frequency of a V279F polymorphism (G/T transversion) in the PAF-AH gene was quantified in 76 Japanese children with KD and 112 healthy Japanese adults using the allele-specific polymerase chain reaction (PCR). Associations between genotype, clinical features, and resistance to intravenous immunoglobulin (IVIG) were investigated in the patients with KD. Plasma PAF-AH activity was measured by using [3H]-acetyl-PAF. There were no significant differences in genotype frequency between patients and controls (P = .51). Compared with the GG (normal genotype) group, significantly more patients in the GT (heterozygous) +TT (homozygous deficient) group required additional IVIG (52% vs 14%, P = .001). The duration of fever and maximum serum C-reactive protein (CRP) levels also were significantly increased in the GT+TT group (P = .012 and .036, respectively), whereas plasma PAF-AH activity was significantly lower (P <.0001). We conclude that the V279F polymorphism in the plasma PAF-AH gene and consequent enzymatic deficiency is one of the factors for IVIG nonresponse in Japanese patients with acute KD.

Lack of Association Between Carotid Intima-Media Thickness and PAF-Acetylhydrolase Mass and Activity in Patients with Primary Hyperlipidemia

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

Thyroid Substitution Therapy Induces High-Density Lipoprotein–Associated Platelet-Activating Factor–Acetylhydrolase in Patients with Subclinical Hypothyroidism: A Potential Antiatherogenic Effect

Subclinical hypothyroidism (SH) has been associated with an increased risk of ischemic heart disease, which has been partly attributed to lipid abnormalities. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme associated with lipoproteins (both low-density lipoproteins [LDL], and high-density lipoproteins [HDL]). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. To evaluate qualitative changes in lipoprotein metabolism with respect to PAF-AH and PON1 activities in patients with SH before and after the restoration of euthyroidism. We determined the PAF-AH activity in plasma and on HDL and PON1 activities as well as the lipid profile patients with SH at baseline and after 6 months of levothyroxine substitution therapy. Thirty normolipidemic healthy individuals comprised the control group. Compared to controls, patients with SH showed higher levels of total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B. Triglycerides were significantly reduced after levothyroxine treatment. Patients with SH exhibited higher plasma baseline PAF-AH activity (63.0 +/- 16.5 versus 44.3 +/- 9.5 nmol/mL per minute p < 0.0001) and lower baseline HDL associated PAF-AH (2.9 +/- 1.1 versus 3.6 +/- 0.9 nmol/mL per minute p = 0.02) compared to the control group. PON1 activities were similar in both groups. Levothyroxine treatment had no effect on plasma PAF-AH activity or PON1 activities but resulted in a significant elevation of HDL-associated PAF-AH activity (from 2.9 +/- 1.1 to 3.5 +/- 1.0 nmol/mL per minute, p = 0.003). Patients with SH exhibit increased plasma PAF-AH activity and low HDL-associated PAF-AH activity. Levothyroxine induces a significant increase in HDL-PAF-AH activity. This action may represent a potential antiatherogenic effect of thyroid replacement therapy.

Effects of antihypertensive and hypolipidemic drugs on plasma and high-density lipoprotein-associated platelet activating factor-acetylhydrolase activity.

Human plasma platelet activating factor acetylhydrolase (PAF-AH) is a phospholipase A2 primarily associated with low-density lipoprotein (LDL). PAF-AH activity has also been found on high-density lipoprotein (HDL). Most of the clinical studies that have investigated the plasma levels of PAF-AH activity in cardiovascular disease have involved patients who were under treatment with various drugs, such as antihypertensive or hypolipidemic agents. However, the influence of these drugs on the enzyme activity has not been adequately studied. We evaluated the effects of representative antihypertensive and hypolipidemic drugs on the total plasma, as well as on the HDL-associated PAF-AH activity, in 121 patients with essential hypertension and in 90 patients with dyslipidemias of type IIA or type IIB. Serum lipids and enzymatic activities were determined at baseline and after 3 months of treatment. The administration of lacidipine (4 mg, n = 21), valsartan (80 mg, n = 26), indapamide (2.5 mg, n = 20), benazepril (20 mg, n = 20), or atenolol (50 mg, n = 34) did not affect either the total plasma- or the HDL-associated PAF-AH activity. In contrast, treatment with fluvastatin (40 mg, n = 50) or ciprofibrate (100 mg, n = 40) reduced by 25% plasma PAF-AH activity (P <.001) associated with a decrease in serum levels of total cholesterol and LDL-cholesterol (P <.001). Furthermore, ciprofibrate induced an increase by 26% in HDL-associated PAF-AH activity (P =.004) along with an increase in serum HDL-cholesterol levels (P =.02). Among all types of drugs studied, only those that significantly affect lipid metabolism, such as statins and fibrates, significantly influence PAF-AH activity in human plasma.

PAF responsiveness in Japanese subjects with plasma PAF acetylhydrolase deficiency

Approximately 4% of the Japanese population genetically lack plasma platelet activating factor acetylhydrolase (PAF-AH) and show a higher prevalence of thromboembolic disease, but whether they are susceptible to another PAF-related disease, asthma, remains controversial. To determine the role of plasma PAF-AH in airway physiology, we performed PAF bronchoprovocation tests in 8 plasma PAF-AH-deficient subjects and 16 control subjects. Serial inhalation of PAF (1–1000 μg/ml) concentration-dependently induced acute bronchoconstriction, but there was no significant difference between PAF-AH-deficient and control subjects (11.7 ± 4.6% vs. 9.6 ± 2.8% decrease in forced expiratory volume in 1 s). Transient neutropenia after single inhalation of PAF (1000 μg/ml) showed no significant difference between the groups either in its magnitude (72 ± 11% vs. 65 ± 9% decrease) or duration (4.1 ± 1.0 vs. 3.3 ± 0.8 min). In conclusion, a lack of plasma PAF-AH activity alone does not augment physiological responses to PAF in the airway.

Platelet-activating factor acetylhydrolase gene polymorphism and its activity in Japanese patients with multiple sclerosis

We evaluated the association of the plasma platelet-activating factor acetylhydrolase (PAF-AH) gene polymorphism (G 994→T) and PAF-AH activity with susceptibility and severity of multiple sclerosis (MS) in Japanese. DNA was collected from 216 patients with clinically definite MS (65 opticospinal MS (OS-MS) and 151 conventional MS (C-MS)) and from 213 healthy controls. The missense mutation G 994→T that disrupts the PAF-AH activity was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No statistically significant difference in the frequency of genotypes and alleles of the plasma PAF-AH polymorphism was observed among OS-MS patients, C-MS patients and healthy controls. However, the missense mutation tended to be associated with the severity of OS-MS, especially in females (GT/TT genotypes; 51.7% in female rapidly progressive OS-MS vs. 26.6% in female controls, p=0.0870). Moreover, PAF-AH activities were significantly lower in MS than in controls, irrespective of clinical subtypes, among those carrying the identical polymorphism in terms of nucleotide position 994 of the PAF-AH gene. These findings suggest that the PAF-AH gene missense mutation has no relation to either susceptibility or severity of C-MS, yet its activity is down-regulated, and that the mutation has no relation with susceptibility of OS-MS, yet it may confer the severity of female OS-MS.

Effect of hypolipidemic drugs on lipoprotein-associated platelet activating factor acetylhydrolase: Implication for atherosclerosis

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.

Single nucleotide polymorphism (G994→T) in the plasma platelet-activating factor-acetylhydrolase gene is associated with graft patency of femoropopliteal bypass

Background. Plasma platelet-activating factor-acetylhydrolase (PAF-AH) is known to catalyze platelet-activating factor (PAF). The single nucleotide polymorphism (SNP) of plasma PAF-AH gene (G994 →T in exon 9) is associated with a decreased level of plasma PAF-AH activity. This study analyzed the risk of the SNP on graft occlusion of femoropopliteal bypass in patients with atherosclerotic occlusive disease. Methods. We retrospectively assessed the patency of 50 above-knee femoropopliteal bypass grafting in 50 patients. Genomic DNA was analyzed for the mutant allele. Plasma PAF-AH activity was measured by radioimmunoassay. Results. The 10-year cumulative primary patency of the bypass was 78.5% in GG (normal genotype) and 50.0% in GT (heterozygous) or TT (homozygous deficient) (P <.05, Kaplan-Meier method). The relative risk of graft failure in GT or TT genotypes was 1.68 (P =.08, Cox proportional hazards model). PAF-AH activity (nmol/min/50 μL) was 1.92 ± 0.82 in patients with patent grafts and 1.42 ± 0.47 in those with occluded grafts (mean ± standard deviation; P <.05, unpaired t test). Conclusions. The SNP of plasma PAF-AH was associated with a decreased primary graft patency of above-knee femoropopliteal bypass. The risk of graft failure may increase when patients have the SNP. To confirm the independent risk of graft failure by the SNP, further study is necessary and prospective study should be performed.(Surgery 2002;132:66-71.)

Association of a G994 -->T missense mutation in the plasma platelet-activating factor acetylhydrolase gene with risk of abdominal aortic aneurysm in Japanese.

To investigate a possible association with plasma platelet activating factor acetylhydrolase (PAF-AH) gene mutation with the risk of abdominal aortic aneurysm (AAA). Plasma platelet activating factor acetylhydrolase is known to catalyze platelet activating factor (PAF), thereby inactivating its inflammatory function. Deficiency of this enzyme is caused by a missense mutation (G994 -->T) in exon 9 of the plasma PAF-AH gene. We did a case-control study including 131 patients (median age 73.4 [range 50-84] years) and 106 controls matched for age and sex. Genomic DNA was analyzed for the mutant allele by a specific polymerase-chain reaction. Plasma PAF-AH activity was measured in both groups. The frequency of the mutant allele (T allele) in the plasma PAF-AH gene in AAA patients was significantly higher than in control subjects. The association of the missense mutation with AAA was statistically significant and independent of other risk factors. Among AAA patients with normal genomic type, plasma PAF-AH activity was strongly correlated to the plasma concentration of low density lipoprotein cholesterol (LDL-C), while the correlation was not observed among AAA patients with heterozygotes genotype. Patients having AAA with both T allele and hyperlipidemia were more likely to have other atherosclerotic diseases such as ischemic heart disease, stroke and peripheral arterial occlusive diseases than patients with the normal genomic type and normal lipid level. The genetic mutation of plasma PAF-AH gene appear to be an independent risk factor for AAA. Our findings need to be confirmed in a larger, prospective study including patients from different populations.

Plasma platelet-activating factor acetylhydrolase deficiency is associated with atherosclerotic occlusive disease in Japan

Purpose: Plasma platelet-activating factor acetylhydrolase (PAF-AH) is known to catalyze platelet-activating factor, thereby inactivating its inflammatory function. Deficiency of this enzyme is caused by a missense (G994→T) in exon 9 of the plasma PAF-AH gene. In this study, we investigated a possible association of this mutation with the risk of atherosclerotic occlusive disease (AO) in Japanese patients. Methods: We studied 104 patients with AO. The control group consisted of 114 subjects matched for age and sex. Plasma PAF-AH activity was measured in the patients with AO. Results: The prevalence of the mutant genotype (GT + TT ) was significantly more frequent in patients with AO than in control subjects (36.5% vs 23.7%; P <.05). Among the patients with AO, those with the mutant allele had significantly more risk factors of prior stroke or ischemic heart disease than patients with normal genotypes. Plasma PAF-AH activity was higher in patients with AO than in control subjects in normal genotype subgroups. Conclusions: The missense (G994→T) in exon 9 of the plasma PAF-AH gene is associated with AO in Japanese people. (J Vasc Surg 2000;32:263-7.)