title: FOXO1 impairs whereas statin protects endothelial function in diabetes through reciprocal regulation of Kruppel-like factor 2.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  Exposure 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.
  
  
  CONCLUSIONS
  Suppression 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.
authors.affiliation: National Research Laboratory of Cardiovascular Stem Cell Niche, Seoul,  Korea.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Seock-Won
authors.initials: SW
authors.lastname: Youn
authors.forename: Hyun-Jai
authors.initials: HJ
authors.lastname: Cho
authors.forename: Yoo-Wook
authors.initials: YW
authors.lastname: Kwon
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Oh
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001483:Base Sequence; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019610:Cytoprotection; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D020334:Rats, Inbred OLETF; D013997:Time Factors; D014162:Transfection; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096161:KLF2 protein, human; C543921:Klf2 protein, rat; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011758:Pyrroles; D014665:Vasodilator Agents; C074639:Foxo1 protein, rat; D000069059:Atorvastatin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D008798:Mevalonic Acid