FOXO1 impairs whereas statin protects endothelial function in diabetes through reciprocal regulation of Krüppel-like factor 2

Hae Young Lee, Seock Won Youn, Hyun Jai Cho, Yoo Wook Kwon, Sae Won Lee, Sung Jin Kim, Young Bae Park, Byung Hee Oh, Hyo Soo Kim

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Aims Krüppel-like factor 2 (KLF2) is implicated as a key molecule maintaining endothelial function. This study was designed to evaluate the reciprocal regulation of KLF2 by the forkhead transcription factor FOXO1, and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin, in hyperglycaemic conditions.Methods and resultsExposure of human umbilical vein endothelial cells to 30 mM glucose activated FOXO1 and suppressed KLF2. These effects were reversed by FOXO1 small interfering RNA. Adenoviral transfection of constitutively active FOXO1 suppressed KLF2 expression. Interestingly, atorvastatin inhibited FOXO1 by increasing phosphorylation and also by inhibiting nuclear localization and replenished KLF2 in high-glucose conditions. This effect of atorvastatin was attenuated by mevalonate. Chromatin immunoprecipitation analysis demonstrated that glucose increased whereas atorvastatin decreased FOXO1 binding to the promoter region of the KLF2 gene. In the vessels of Otsuka Long-Evans Tokushima Fatty rats, animal models of type 2 diabetes, FOXO1 was activated and KLF2 was suppressed, and this was reversed by atorvastatin treatment. The arteries from Otsuka Long-Evans Tokushima Fatty rats showed impairment of endothelium-dependent vasodilatation, and both atorvastatin and KLF2 gene therapies restored it.ConclusionsSuppression of KLF2 by FOXO1 may be a plausible mechanism of diabetic endothelial dysfunction. High-glucose-induced, FOXO1-mediated KLF2 suppression was reversed by atorvastatin, suggesting that intensive statin treatment could be a therapeutic option in diabetic vascular dysfunction.

Original languageEnglish (US)
Pages (from-to)143-152
Number of pages10
JournalCardiovascular Research
Volume97
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Diabetes
  • FOXO1
  • Krüppel-like factor 2
  • Statin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Lee, H. Y., Youn, S. W., Cho, H. J., Kwon, Y. W., Lee, S. W., Kim, S. J., Park, Y. B., Oh, B. H., & Kim, H. S. (2013). FOXO1 impairs whereas statin protects endothelial function in diabetes through reciprocal regulation of Krüppel-like factor 2. Cardiovascular Research, 97(1), 143-152. https://doi.org/10.1093/cvr/cvs283