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(Circulation. 2004;110:3472-3479.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

Functional Interplay Between the Macrophage Scavenger Receptor Class B Type I and Pitavastatin (NK-104)

Jihong Han, PhD; Michael Parsons, MD; Xiaoye Zhou, MD; Andrew C. Nicholson, DVM, PhD; Antonio M. Gotto, Jr, MD, DPhil; David P. Hajjar, PhD

From the Center of Vascular Biology and Department of Pathology (J.H., X.Z., A.C.N., D.P.H.) and the Department of Medicine (M.P., A.M.G.), Weill Medical College of Cornell University, New York, NY.

Correspondence to Jihong Han, PhD, Center of Vascular Biology/Department of Pathology, Weill Medical College of Cornell University, 1300 York Ave, New York, NY 10021. E-mail jhan{at}med.cornell.edu

Received February 2, 2004; de novo received March 25, 2004; revision received September 3, 2004; accepted September 14, 2004.

Background— Scavenger receptor class B type I (SR-BI), a receptor for high-density lipoprotein (HDL), plays an important role in the bidirectional cholesterol exchange between cells and HDL particles and the atherosclerotic lesion development. Enhancement of SR-BI expression significantly reduces, whereas lack of SR-BI expression accelerates, the atherosclerotic lesion development in proatherogenic mice. Statins, a class of inhibitors for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, significantly suppress de novo cholesterol synthesis and reduce the incidence of coronary heart disease. Statins also display multiple pleiotropic effects independently of cholesterol synthesis in the vascular cells. Here, we investigated the effects of pitavastatin (NK-104), a newly synthesized statin, on macrophage SR-BI expression.

Methods and Results— We found that pitavastatin significantly increased SR-BI mRNA and protein expression in a macrophage cell line in a concentration- and time-dependent manner. It also increased SR-BI expression in both mouse peritoneal and human monocyte-derived macrophages. Associated with increased SR-BI expression, pitavastatin enhanced macrophage HDL binding, uptake of [¹⁴C]cholesteryl oleate/HDL, and efflux of [³H]cholesterol to HDL. Pitavastatin abolished the inhibition of macrophage SR-BI expression by cholesterol biosynthetic intermediates. It also restored SR-BI expression inhibited by lipopolysaccharide and tumor necrosis factor- through its inactivation of the transcription factor nuclear factor-B.

Conclusions— Our data demonstrate that pitavastatin can stimulate macrophage SR-BI expression by reduction of cholesterol biosynthetic intermediates and antiinflammatory action and suggest additional pleiotropic effects of statins by which they may reduce the incidence of coronary heart disease.

Key Words: statins • macrophages • scavenger receptors • lipoproteins

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