on March 20, 2003
Published online before print March 20, 2003, doi: 10.1161/01.ATV.0000067701.09398.18
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Submitted on September 26, 2002
Accepted on March 4, 2003
Human Plasma Platelet-Activating Factor Acetylhydrolase Binds to All the Murine Lipoproteins, Conferring Protection Against Oxidative Stress
Hiroshi Noto ;
From the Department of Metabolic Diseases (H.N., M.H., N.I.-O., H.S., M.T., S.K., K.T.) and the Department of Clinical Laboratory Medicine (Y.H.), Graduate School of Medicine, University of Tokyo; Faculty of Pharmaceutical Sciences (K.K.), Teikyo University; the Department of Gene Therapy (Y.Y.), Gifu International Institute of Biotechnology; Diagnostic Research & Development Department (T.K.), R&D Division, Nesco Co, Azwell Inc; and the Department of Internal Medicine (M.K.), Tokyo Teishin Hospital, Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: kazuhisa-tky{at}umin.ac.jp.
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.
Conclusions--These results suggest that human plasma PAF-AH exerts an antiatherogenic effect by binding to all the lipoproteins and thereby protecting them from oxidation, producing less proatherogenic lipoproteins and preserving HDL functions.
Key words: platelet-activating factor acetylhydrolase • oxidative stress • adenovirus • foam cell formation • cholesterol efflux
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