Abstract 16640: Foxo1 Impairs Whereas Statin Protects Endothelial Function in Hyperglycemic Conditions Through Reciprocal Regulation of Kruppel-like Factor 2
Endothelial dysfunction is an initial critical factor in the pathogenesis of diabetic vascular complications. Krüppel-like factor 2(KLF2) is implicated as a key molecule maintaining endothelial function. We investigated the role of a forkhead transcription factor, FOXO1, and HMG-CoA reductase inhibitor in KLF2 regulation in hyperglycemic conditions. FOXO1 expression was increased by 190% (p<0.05), whereas KLF2 and eNOS expression were decreased by 60% (p<0.05) and by 70% (p<0.05) in human umbilical vein endothelial cells incubated in 30 mM glucose for 24 h, all of which were completely reversed by FOXO1 siRNA. Adenovirus-mediated overexpression of FOXO1 decreased the expression of KLF2 and eNOS by 49% and 69% (p<0.05). Atorvastatin (1 μM) inhibited FOXO1 not only by increasing phosphorylation by 170% (p<0.05) but also by degrading FOXO1 protein by 70% (p<0.05). Atorvastatin also restored KLF2 expression suppressed in high glucose conditions similar to the control level (92.3 ± 3.4%, p=0.1), which was totally blocked by co-incubation with mevalonate. A chromatin immunoprecipitation analysis demonstrated that glucose and atorvastatin reciprocally regulated KLF2 at transcription level by modulating binding of FOXO1 to its promoter regions at -609 and -754bp. In vivo experiment with the OLETF rats, the animal models of type 2 diabetes, FOXO1 in the endothelial lining of the thoracic aorta was mainly located in the nucleus and KLF2 (41.5±3.9%, p<0.05) and eNOS (62.5 ± 1.8%, p<0.05) expressions were significantly decreased compared with the control LETO rats, which were reversed by atorvastatin administered with 5 mg/kg/day for > 4 weeks (KLF2 expression by 157.3 ± 37% and eNOS expression by 112.5 ± 27% of the control values). The endothelium-dependent vasodilation with acetylcholine were significantly decreased in OLETF rats (23.4 ± 22.8% of the LETO rats, p<0.05), which was significantly improved both by atorvastatin (67.3 ± 0.5%, p<0.05) and by adenovirus-mediated overexpression of KLF2 (61.4 ± 15.4%, p<0.05). In conclusion, KLF2 suppression by FOXO1 may be a plausible mechanism of endothelial dysfunction in diabetes. The findings of this study suggest implication of intensive statin treatment in preventing diabetic vasculopathy.
- © 2011 by American Heart Association, Inc.