Jihong Han, Xiaoye Zhou, T. Yokoyama
Feb 17, 2004
Citations
2
Influential Citations
95
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Quality indicators
Journal
Circulation: Journal of the American Heart Association
Abstract
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-&ggr; (PPAR&ggr;) 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&ggr; mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPAR&ggr; phosphorylation and increased the ratio of phosphorylated PPAR&ggr; to nonphosphorylated PPAR&ggr;. Conclusions—The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPAR&ggr;-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.