Platelet-Activating Factor Acetylhydrolases:  Broad Substrate Specificity and Lipoprotein Binding Does Not Modulate the Catalytic Properties of the Plasma Enzyme

Min, Jaehong; Wilder, Cheryl; Aoki, Junken; Arai, Hiroyuki; Inoue, Kazuhide; Paul, Leland S.; Gelb, Michael H.

doi:10.1021/bi002600g

Cited by 64 publications

(53 citation statements)

References 44 publications

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“…Treatment with fenofibrates reduced PAF-AH activity associated with small dense LDL and, in some cases, increased the HDL-associated activity (56). We previously reported that HDL-and LDL-associated PAF-AH behave identically in optimized assays designed to measure initial rates of hydrolysis, a finding supported by other studies that used similar assay conditions (13,58). In contrast, when we and FIGURE 3.…”

Section: Discussionsupporting

confidence: 69%

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

Gardner

Reichert

Topham

et al. 2008

Journal of Biological Chemistry

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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.

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Section: Discussionsupporting

confidence: 69%

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

Gardner

Reichert

Topham

et al. 2008

Journal of Biological Chemistry

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“…5 Plasma PAF-AH (pPAF-AH) has a relatively broad substrate specificity for phospholipids, and can catalyze and inactivate not only PAF but also PAF-like oxidized lipids. 6 This enzyme activity has been reported to correlate with several inflammatory diseases such as asthma, 7,8 systemic lupus erythematosus 9 and juvenile rheumatoid arthritis. 10 Furthermore, previous reports have revealed that the polymorphism of pPAF-AH gene (PLA2G7) influences its activity.…”

Section: Introductionmentioning

confidence: 98%

Association of PLA2G7 polymorphisms with carotid atherosclerosis in hypertensive Japanese

et al. 2009

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Although the plasma platelet-activating factor-acetylhydrolase (pPAF-AH) gene (PLA2G7) polymorphisms are reportedly associated with atherosclerotic diseases, their effects in hypertensive patients have not been well examined. Thus, we genotyped V279F, a loss-of-function mutation commonly seen in the Japanese, and I198T and A379V commonly seen in Caucasians, and investigated the (1) ethnic differences in the frequencies and (2) association of these variants with prevalence of carotid plaque in 733 treated hypertensive Japanese patients. The distribution of V279F (V allele 75.1% and F allele 24.9%) in hypertensive patients was similar to that previously reported in the healthy Japanese; however, allele frequencies of I198T (I allele 71.7% and T allele 28.3%) and A379V (A allele 84.7% and V allele 15.3%) were markedly different from those reported in Caucasians. In addition, V279F and I198T showed a strong linkage disequilibrium (D ¢¼1.0, r 2 ¼0.89). The phenotypes showed no difference among genotypes for each polymorphism except for the blood pressure level in I198T in women. Carotid plaque was significantly more prevalent in subjects with 279F and 198T than in those with the wild type among men but not women, whereas A379V did not affect it. In multivariate logistic regression analyses, 279F and 198T were detected as an independent risk factor even after adjustments for other atherosclerotic risk factors in men. Taken together, our data suggest an ethnic difference and the possible involvement of genetic polymorphisms of PLA2G7 in the prevalence of carotid atherosclerosis in the hypertensive Japanese, especially in men.

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“…PAF-AH II is a single 40-kDa polypeptide (23). This isoenzyme recognizes both PAF and acyl analogs of PAF with moderate length sn-2 chains as well as short chain diacylglycerols, triacylglycerols, and acetylated alkanols (24). Ectopic expression reduces cell death triggered by oxidative stress (25,26).…”

mentioning

confidence: 99%

“…Plasma PAF-AH is a 45-kDa monomer secreted into circulation by endothelial and hematopoietic cells (27,28). The enzyme recognizes PAF and PAF analogs with short to medium sn-2 chains including oxidatively cleaved long chain polyunsaturated acyl chains (24). In vitro, recombinant plasma PAF-AH or ectopic expression protects cells from excitotoxicity or hypercholesterolemia (29 -31).…”

mentioning

confidence: 99%

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

Bonin¹,

Ryan²,

Migahed³

et al. 2004

Journal of Biological Chemistry

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Platelet-activating factor (PAF) is an important mediator of cell loss following diverse pathophysiological challenges, but the manner in which PAF transduces death is not clear. Both PAF receptor-dependent and -independent pathways are implicated. In this study, we show that extracellular PAF can be internalized through PAF receptor-independent mechanisms and can initiate caspase-3-dependent apoptosis when cytosolic concentrations are elevated by ϳ15 pM/cell for 60 min. Reducing cytosolic PAF to less than 10 pM/cell terminates apoptotic signaling. By pharmacological inhibition of PAF acetylhydrolase I and II (PAF-AH) activity and down-regulation of PAF-AH I catalytic subunits by RNA interference, we show that the PAF receptor-independent death pathway is regulated by PAF-AH I and, to a lesser extent, by PAF-AH II. Moreover, the anti-apoptotic actions of PAF-AH I are subunit-specific. PAF-AH I ␣ 1 regulates intracellular PAF concentrations under normal physiological conditions, but expression is not sufficient to reduce an acute rise in intracellular PAF levels. PAF-AH I ␣ 2 expression is induced when cells are deprived of serum or exposed to apoptogenic PAF concentrations limiting the duration of pathological cytosolic PAF accumulation. To block PAF receptor-independent death pathway, we screened a panel of PAF antagonists (CV-3988, CV-6209, BN 52021, and FR 49175). BN 52021 and FR 49175 accelerated PAF hydrolysis and inhibited PAF-mediated caspase 3 activation. Both antagonists act indirectly to promote PAF-AH I ␣ 2 homodimer activity by reducing PAF-AH I ␣ 1 expression. These findings identify PAF-AH I ␣ 2 as a potent antiapoptotic protein and describe a new means of pharmacologically targeting PAF-AH I to inhibit PAF-mediated cell death.Platelet-activating factor (PAF, 1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a key mediator of neuronal death in ischemia, encephalitis, epileptic seizure, meningitis, and human immunodeficiency virus-1 dementia in vivo and participates in etoposide-, prion-, and ␤-amyloid-induced cell death in vitro (1-7). In the periphery, pathological increases in PAF concentrations underlie cytotoxicity in chronic inflammatory dermatoses and lethality in systemic anaphylaxis (8, 9). Although the majority of PAF effects are understood to be transduced by its G-protein-coupled receptor (PAFR) (10), PAFR signaling has been shown to be both pro-and anti-apoptotic. Ectopic PAFR expression exacerbates cell death induced by etoposide and mitomycin C but protects cells from tumor necrosis factor ␣, TRAIL, and extracellular PAF (6,7,11,12). These opposing effects likely depend upon the relative ratio of NF-B-dependent pro-and anti-apoptotic gene products elicited in different cell types in response to the combination of an external apoptotic inducer and PAF (6).Accumulating evidence points to additional PAF signaling pathways transduced independently of PAFR (11, 13-17). PAFR-negative cells undergo apoptosis when extracellular PAF concentrations reach 100 nM and necrosis when PAF levels e...

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Platelet-Activating Factor Acetylhydrolases: Broad Substrate Specificity and Lipoprotein Binding Does Not Modulate the Catalytic Properties of the Plasma Enzyme

Cited by 64 publications

References 44 publications

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

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

Association of PLA2G7 polymorphisms with carotid atherosclerosis in hypertensive Japanese

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

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