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

Jiyuan Zhao, Selvamuthu K. Natarajan, Nicolas Chronos, Jai Pal Singh

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)825-839
Number of pages15
JournalCellular and Molecular Biology Letters
Volume20
Issue number5
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Kruppel-Like Transcription Factors
Terpenes
Metabolic Networks and Pathways
Gene expression
CC Chemokines
Chemokine CCL2
Chemokine Receptors
Gene Expression
Protein C
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Genes
Macrophages
Mevalonic Acid
cerivastatin
Transcription
Small Interfering RNA
Inflammation
Messenger RNA

Keywords

  • CCR2
  • Cerivastatin
  • Gene expression
  • Inflammation
  • Isoprenoid pathway
  • KLF2
  • Macrophage
  • MCP-1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cerivastatin represses atherogenic gene expression through the induction of KLF2 via isoprenoid metabolic pathways. / Zhao, Jiyuan; Natarajan, Selvamuthu K.; Chronos, Nicolas; Singh, Jai Pal.

In: Cellular and Molecular Biology Letters, Vol. 20, No. 5, 01.12.2015, p. 825-839.

Research output: Contribution to journalArticle

Zhao, Jiyuan ; Natarajan, Selvamuthu K. ; Chronos, Nicolas ; Singh, Jai Pal. / Cerivastatin represses atherogenic gene expression through the induction of KLF2 via isoprenoid metabolic pathways. In: Cellular and Molecular Biology Letters. 2015 ; Vol. 20, No. 5. pp. 825-839.
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