RTEF-1 attenuates blood glucose levels by regulating insulin-like growth factor binding protein-1 in the endothelium.

Rationale: Related transcriptional enhancer factor-1 (RTEF-1) plays an important role in endothelial cell function by regulating angiogenesis; however, the mechanism underlying the role of RTEF-1 in the endothelium in vivo is not well defined. Objective: We investigated the biological functions of RTEF-1 by disrupting the gene that encodes it in mice endothelium -specific RTEF-1-deficient transgenic mice (RTEF-1(-/-)). Methods and Results: RTEF-1(-/-) mice showed significantly increased blood glucose levels and insulin resistance, accompanied by decreased levels of insulin-like growth factor binding protein-1 (IGFBP-1) mRNA in the endothelium and decreased serum IGFBP-1 levels. Additionally, the RTEF-1(-/-) phenotype was exacerbated when the mice were fed a high-fat diet, which correlated with decreased IGFBP-1 levels. In contrast, vascular endothelial cadherin/RTEF-1-overexpressing1 transgenic mice (VE-Cad/RTEF1) demonstrated improved glucose clearance and insulin sensitivity in response to a high-fat diet. Furthermore, we demonstrated that RTEF-1 upregulates IGFBP-1 through selective binding and promotion of transcription from the insulin response element site. Insulin prevented RTEF-1 expression and significantly inhibited IGFBP-1 transcription in endothelial cells in a dose-dependent fashion. Conclusions: To the best of our knowledge, this is the first report demonstrating that RTEF-1 stimulates promoter activity through an insulin response element and also mediates the effects of insulin on gene expression. These results show that RTEF-1-stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels. These findings provide the basis for novel insights into the transcriptional regulation of IGFBP-1 and contribute to our understanding of the role of vascular endothelial cells in metabolism. (Circ Res. 2012;111:991-1001.)