Statins exert endothelial atheroprotective effects via the KLF2 transcription factor

Kush M. Parmar, Vinod Nambudiri, Guohao Dai, Harry Larman, Michael A. Gimbrone, Guillermo García-Cardeña

Research output: Contribution to journalArticle

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, stating, have been shown to positively impact vascular function independent of their plasma lipid-lowering action. Several of these beneficial effects involve modulation of gene expression. Here we explored whether the transcription factor Kruppel-like factor 2 (KLF2), a biomechanically activated gene we recently identified as port of the endothelial "atheroprotective phenotype," is regulated by statins and whether this mechanism is important for the non-lipid lowering beneficial effects mediated by these drugs in endothelium. The mRNA levels of KLF2 in human umbilical vein endothelial cells increased in the presence of various statins. KLF2 induction was observed within 8 h after drug treatment and remained elevated for at least 24 h. This statin effect on KLF2 expression was reversed by addition of mevalonate and its downstream metabolite geranygeranyl pyrophosphate. Furthermore, inhibition of protein geranylgeranylation with GGTI-298 significantly induced KLF2 levels, whereas inhibition of farnesylation did not. Statin-mediated KLF2 expression was followed by the up-regulation of several of its downstream transcriptional targets. Using small interfering RNA to block KLF2 expression, we demonstrated that this transcription factor is necessary for the statin-mediated regulation of several pathophysiologically relevant genes. These results strongly implicate KLF2 as a transcriptional regulator of the statin-mediated effects in vascular endothelium and provide a novel mechanism for the well established non-lipid lowering beneficial cardiovascular effects of statins.

Original languageEnglish (US)
Pages (from-to)26714-26719
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number29
DOIs
StatePublished - Jul 22 2005
Externally publishedYes

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Kruppel-Like Transcription Factors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Transcription Factors
Genes
Protein Prenylation
Prenylation
Drug therapy
Mevalonic Acid
Transcription factors
Endothelial cells
Human Umbilical Vein Endothelial Cells
Vascular Endothelium
Metabolites
Gene expression
Pharmaceutical Preparations
Small Interfering RNA
Endothelium
Blood Vessels
Oxidoreductases
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Parmar, K. M., Nambudiri, V., Dai, G., Larman, H., Gimbrone, M. A., & García-Cardeña, G. (2005). Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. Journal of Biological Chemistry, 280(29), 26714-26719. https://doi.org/10.1074/jbc.C500144200

Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. / Parmar, Kush M.; Nambudiri, Vinod; Dai, Guohao; Larman, Harry; Gimbrone, Michael A.; García-Cardeña, Guillermo.

In: Journal of Biological Chemistry, Vol. 280, No. 29, 22.07.2005, p. 26714-26719.

Research output: Contribution to journalArticle

Parmar, KM, Nambudiri, V, Dai, G, Larman, H, Gimbrone, MA & García-Cardeña, G 2005, 'Statins exert endothelial atheroprotective effects via the KLF2 transcription factor', Journal of Biological Chemistry, vol. 280, no. 29, pp. 26714-26719. https://doi.org/10.1074/jbc.C500144200
Parmar, Kush M. ; Nambudiri, Vinod ; Dai, Guohao ; Larman, Harry ; Gimbrone, Michael A. ; García-Cardeña, Guillermo. / Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 29. pp. 26714-26719.
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