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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:424.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Pitavastatin Inhibits Remnant Lipoprotein-Induced Macrophage Foam Cell Formation Through ApoB48 Receptor–Dependent Mechanism

Akio Kawakami; Mariko Tani; Tsuyoshi Chiba; Katsumasa Yui; Shohei Shinozaki; Katsuyuki Nakajima; Akira Tanaka; Kentaro Shimokado; Masayuki Yoshida

From the Departments of Geriatrics and Vascular Medicine (A.K., M.T., T.C., K.Y., S.S., K.S., M.Y.) and Medical Biochemistry (A.K., M.T., M.Y.), Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Japan Immunoresearch Laboratories (K.N.), Takasaki, Japan; and the Department of Health and Nutrition (A.T.), College of Human Environmental Studies, Kanto-Gakuin University, Yokohama, Japan.

Correspondence to Masayuki Yoshida, MD, Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bldg. D-809, Bunkyo-ku, Tokyo 1138519 Japan. E-mail masa.vasc{at}tmd.ac.jp

Objective— Atherogenic remnant lipoproteins (RLPs) are known to induce foam cell formation in macrophages in vitro and in vivo. We examined the involvement of apoB48 receptor (apoB48R), a novel receptor for RLPs, in that process in vitro and its potential regulation by pitavastatin.

Methods and Results— THP-1 macrophages were incubated in the presence of RLPs (20 mg cholesterol/dL, 24 hours) isolated from hypertriglyceridemic subjects. RLPs significantly increased intracellular cholesterol ester (CE) and triglyceride (TG) contents (4.8-fold and 5.8-fold, respectively) in the macrophages. Transfection of THP-1 macrophages with short interfering RNA (siRNA) against apoB48R significantly inhibited RLP-induced TG accumulation by 44%. When THP-1 macrophages were pretreated with pitavastatin (5 µmol/L, 24 hours), the expression of apoB48R was significantly decreased and RLP-induced TG accumulation was reduced by 56%. ApoB48R siRNA also inhibited TG accumulation in THP-1 macrophage induced by ß–very-low-density lipoprotein derived from apoE–/– mice by 58%, supporting the notion that apoB48R recognizes and takes-up RLPs in an apoE-independent manner.

Conclusions— RLPs induce macrophage foam cell formation via apoB48R. Pitavastatin inhibits RLP-induced macrophage foam cell formation. The underlying mechanism involves, at least in part, inhibition of apoB48R-dependent mechanism. Our findings indicate a potential role of apoB48R in atherosclerosis.

RLPs induced macrophage foam cell formation via apoB48R. Pitavastatin inhibited RLP-induced macrophage foam cell formation, at least in part, via inhibition of apoB48R expression. Our findings indicate a potential role of apoB48R in atherosclerosis.

Key Words: remnant lipoproteins • foam cell formation • apoB48 receptor • statin • atherosclerosis

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