title: Cerivastatin represses atherogenic gene expression through the induction of KLF2 via isoprenoid metabolic pathways.
abstract: Earlier clinical studies have reported that cerivastatin has an anti-atherosclerotic 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.
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Zhao
authors.forename: Selvamuthu K
authors.initials: SK
authors.lastname: Natarajan
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chronos
authors.forename: Jai Pal
authors.initials: JP
authors.lastname: Singh
mesh_terms: D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008798:Mevalonic Acid / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D013729:Terpenes / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054390:Receptors, CCR2; D012717:Sesquiterpenes; D013729:Terpenes; C004808:farnesyl pyrophosphate; C086276:cerivastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid