Published Online
on November 22, 2004

A more recent version of this article appeared on November 30, 2004

This Article Full Text (PDF) All Versions of this Article: 110/22/3472    most recent 01.CIR.0000148368.79202.F1v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Han, J. Articles by Hajjar, D. P. Search for Related Content PubMed PubMed Citation Articles by Han, J. Articles by Hajjar, D. P. Related Collections Gene regulation Lipid and lipoprotein metabolism

Submitted on February 2, 2004
Revised on September 3, 2004
Accepted on September 14, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: jhan{at}med.cornell.edu.

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

This article has been cited by other articles:

				T. Kimura, C. Mogi, H. Tomura, A. Kuwabara, D.-S. Im, K. Sato, H. Kurose, M. Murakami, and F. Okajima Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells J. Immunol., November 15, 2008; 181(10): 7332 - 7340. [Abstract] [Full Text] [PDF]

				X. Zhou, W. He, Z. Huang, A. M. Gotto Jr., D. P. Hajjar, and J. Han Genetic Deletion of Low Density Lipoprotein Receptor Impairs Sterol-induced Mouse Macrophage ABCA1 Expression: A NEW SREBP1-DEPENDENT MECHANISM J. Biol. Chem., January 25, 2008; 283(4): 2129 - 2138. [Abstract] [Full Text] [PDF]

				K. Tsuchiya, T. Yoshimoto, Y. Hirono, T. Tateno, T. Sugiyama, and Y. Hirata Angiotensin II induces monocyte chemoattractant protein-1 expression via a nuclear factor-{kappa}B-dependent pathway in rat preadipocytes Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E771 - E778. [Abstract] [Full Text] [PDF]

				C. A. Argmann, J. Y. Edwards, C. G. Sawyez, C. H. O'Neil, R. A. Hegele, J. G. Pickering, and M. W. Huff Regulation of Macrophage Cholesterol Efflux through Hydroxymethylglutaryl-CoA Reductase Inhibition: A ROLE FOR RhoA IN ABCA1-MEDIATED CHOLESTEROL EFFLUX J. Biol. Chem., June 10, 2005; 280(23): 22212 - 22221. [Abstract] [Full Text] [PDF]