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(Circulation. 2004;109:790-796.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Pitavastatin Downregulates Expression of the Macrophage Type B Scavenger Receptor, CD36

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

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

Correspondence to Andrew C. Nicholson, DVM, PhD, Department of Pathology, A-626, Weill Medical College of Cornell University, 1300 York Ave, New York, NY 10021. E-mail nicholso{at}med.cornell.edu

Received October 31, 2002; de novo received August 5, 2003; revision received October 1, 2003; accepted October 6, 2003.

Background— Pitavastatin (NK-104) is a novel inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol biosynthesis. In clinical trials, pitavastatin has been shown to significantly decrease serum LDL cholesterol and triglyceride levels and increase HDL cholesterol. Scavenger receptor-mediated accumulation of oxidized LDL (OxLDL)-derived cholesteryl ester is considered to be a critical step in the development of atherosclerotic foam cell formation. We studied the effect of pitavastatin on CD36 (a class B scavenger receptor) expression by murine macrophages.

Methods and Results— Treatment of J774 cells and murine peritoneal macrophages with pitavastatin decreased CD36 mRNA expression in a dose-dependent manner. Decreased CD36 mRNA was associated with decreased CD36 cell surface protein expression in human THP-1 cells and human monocyte-derived macrophages. Pitavastatin also reduced the increase in CD36 mRNA, cell surface protein, and binding/uptake of OxLDL induced by peroxisome proliferator-activated receptor- (PPAR) ligands and/or OxLDL. Pitavastatin did not alter the half-life of CD36 mRNA, which suggests pitavastatin downregulates CD36 expression by reducing CD36 transcription. In addition, pitavastatin significantly decreased PPAR mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPAR phosphorylation and increased the ratio of phosphorylated PPAR to nonphosphorylated PPAR.

Conclusions— The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPAR-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.

Key Words: antigens, CD36 • macrophages • statins • cholesterol • lipoproteins

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