Human Plasma Platelet-Activating Factor Acetylhydrolase Binds to All the Murine Lipoproteins, Conferring Protection Against Oxidative Stress

Abstract

Objective-Plasma platelet-activating factor (PAF) acetylhydrolase (AH) is an enzyme bound with lipoproteins that degrades not only PAF but also PAF-like oxidized phospholipids that are proposed to promote atherosclerosis. In this study, we investigated the distribution of PAF-AH protein among lipoprotein classes by using adenovirus-mediated gene transfer in mice, and we examined its effects on lipoprotein oxidation and foam cell formation of macrophages. Methods and Results-Adenovirus-mediated overexpression of PAF-AH in mice resulted in a 76-to 140-fold increase in plasma PAF-AH activity. Contrary to the previous report, overexpressed human PAF-AH protein was bound to very low density lipoprotein, intermediate density lipoprotein, low density lipoprotein, and high density lipoprotein (HDL). All the lipoproteins with overexpressed human PAF-AH revealed more resistance against oxidative stress, which was associated with lower levels in autoantibody against oxidized low density lipoprotein in the plasma. In addition, HDL with human PAF-AH inhibited foam cell formation and facilitated cholesterol efflux in macrophages. Key Words: platelet-activating factor acetylhydrolase Ⅲ oxidative stress Ⅲ adenovirus Ⅲ foam cell formation Ⅲ cholesterol efflux P latelet-activating factor (PAF) acetylhydrolase (AH) is a calcium-independent enzyme that degrades PAF, a bioactive phospholipid mediator for allergic and inflammatory processes, to a biologically inactive lyso-PAF. Plasma PAF-AH, 1 of the 3 PAF-AH isoforms identified so far, is produced from macrophages and exists in the plasma in the form bound with lipoproteins; the other 2 isoforms are found only in tissues. Seventy percent to 83% of the plasma PAF-AH protein exists on LDL, and 11% to 30% exists on HDL in human plasma. 1,2 An interchange between the 2 lipoproteins has been reported in plasma PAF-AH. 1 In mice, it has been recognized that PAF-AH is associated primarily with HDL and minimally with VLDL 3,4 and that neither murine PAF-AH nor human PAF-AH has been proposed to bind to murine LDL. 5 An observational study has shown that plasma PAF-AH activity is altered in atherosclerotic diseases. 6 Oxidation of LDL, in which PAF-like oxidized phospholipids are produced on the LDL surface, is one of the key factors in the early stages of atherosclerosis. 7 Besides catalyzing PAF, plasma PAF-AH protein hydrolyzes PAF-like oxidized phospholipids, thereby most likely inactivating the biologically active mediator. However, the products of this reaction include oxidized fatty acids and lysophosphatidylcholine, 8 which are potentially inflammatory mediators that could amplify atherogenesis. Therefore, it is not fully clear whether PAF-AH is antiatherogenic or proatherogenic in humans. There was one report documenting that high PAF-AH activity is associated with an increased risk of coronary artery disease in humans. 6 However, it is not conclusive whether PAF-AH is a causative agent of coronary artery disease or just a marker. A recent animal study demonstrated that overexpressi...

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