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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:829.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Hiroshi Noto; Masumi Hara; Ken Karasawa; Naoyuki Iso-O; Hiroaki Satoh; Masako Togo; Yoshiaki Hashimoto; Yoshiji Yamada; Tetsuya Kosaka; Mitsunobu Kawamura; Satoshi Kimura; Kazuhisa Tsukamoto

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, Tokyo; Faculty of Pharmaceutical Sciences (K.K.), Teikyo University, Kanagawa; the Department of Gene Therapy (Y.Y.), Gifu International Institute of Biotechnology, Gifu; Diagnostic Research & Development Department (T.K.), R&D Division, Nesco Co, Azwell Inc, Osaka; and the Department of Internal Medicine (M.K.), Tokyo Teishin Hospital, Tokyo, Japan.

Correspondence to Kazuhisa Tsukamoto, MD, PhD, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. 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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