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

Jihong Han, Xiaoye Zhou, Toru Yokoyama, David P. Hajjar, Antonio M. Gotto, Andrew C. Nicholson

Research output: Contribution to journalArticle

74 Scopus citations

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-γ (PPARγ) 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 PPARγ mRNA and protein expression. Finally, pitavastatin increased p44/42 mitogen-activated protein kinase activity and PPARγ phosphorylation and increased the ratio of phosphorylated PPARγ to nonphosphorylated PPARγ. Conclusions-The present data demonstrate that pitavastatin prevents OxLDL uptake by macrophages through PPARγ-dependent inhibition of CD36 expression and suggest that pitavastatin could modulate CD36-mediated atherosclerotic foam cell formation.

Original languageEnglish (US)
Pages (from-to)790-796
Number of pages7
JournalCirculation
Volume109
Issue number6
DOIs
StatePublished - Feb 17 2004

Keywords

  • Antigens, CD36
  • Cholesterol
  • Lipoproteins
  • Macrophages
  • Statins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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