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Cellular and Molecular Biology Letters

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1689-1392
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Volume 20, Issue 5

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Cerivastatin represses atherogenic gene expression through the induction of KLF2 via isoprenoid metabolic pathways

Jiyuan Zhao
  • Corresponding author
  • School of Medicine, Ningbo University, Ningbo, Zhejiang, People's Republic of China
  • Saint Joseph’s Translational Research Institute, Atlanta, GA, USA
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  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Selvamuthu K. Natarajan / Nicolas Chronos / Jai Pal Singh
Published Online: 2016-03-05 | DOI: https://doi.org/10.1515/cmble-2015-0049

Abstract

Earlier clinical studies have reported that cerivastatin has an antiatherosclerotic effect that is unique among the statins. In our study, human THP-1 macrophage cells were used to study the effects of various statins on the expressions of the atherosclerotic genes and Kruppel-like factor 2 (KLF2). Cerivastatin significantly inhibited the two atherosclerotic genes, monocyte chemoattractant protein-1 (MCP-1) and C-C chemokine receptor type 2 (CCR2) at both the mRNA and protein levels, while the other statins did not. Accordingly, cerivastatin was also the most potent inducer of KLF2 transcription in the macrophages. An siRNA-induced reduction in KLF2 expression blocked the inhibition of MCP-1 and CCR2 by cerivastatin. When the cells were further treated with mevalonate, farnesylpyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), the effects of cerivastatin on KLF2, MCP-1 and CCR2 were obviously reversed. Thus, the results showed that cerivastatin was a potent inhibitor of the inflammation genes MCP-1 and CCR2 through the induction of KLF2. The regulation of MCP-1, CCR2 and KLF2 by cerivastatin was isoprenoid pathway dependent. Our studies suggest that the effect of cerivastatin on atherosclerotic genes and KLF2 expression may contribute to the cardioprotection observed in reported clinical studies.

Keywords: Cerivastatin; Macrophage; Inflammation; KLF2; MCP-1; CCR2; Gene expression; Isoprenoid pathway

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About the article

Received: 2015-07-02

Accepted: 2015-10-22

Published Online: 2016-03-05

Published in Print: 2015-12-01


Citation Information: Cellular and Molecular Biology Letters, Volume 20, Issue 5, Pages 825–839, ISSN (Online) 1689-1392, DOI: https://doi.org/10.1515/cmble-2015-0049.

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