Abstract
Background and Objective: Cardiovascular disease is the most important complication of type 2 diabetes, however, its underlying mechanism(s) are poorly understood. Our lab previously reported that RTEF-1 is a transcription factor that promotes angiogenesis via up-regulating HIF-1α and VEGF. In addition to these studies, we recently determined that RTEF-1 upregulates insulin-like growth factor binding protein-1 (IGFBP-1) expression in endothelial cells in vitro and in vivo. IGFBPs are key regulators of insulin-like growth factor (IGF) type 1 and 2 bioavailability at the cellular level. In addition, IGFBP-1 is implicated in cardiovascular health, in terms of blood pressure and glucose tolerance. Methods and Results: RTEF-1 upregulates IGFBP-1 expression in endothelial cells in vitro and in vivo through selectively binding and promoting transcription from the insulin response element (IRE) site on the IGFBP-1 promoter, demonstrated by ChIP assays. In addition to insulin inhibition of IGFBP-1 levels, insulin also dose-dependently inhibits RTEF-1 promoter activity (-2.4 ± 0.3-fold) and expression. In vivo data suggest that Tie2-Cre:RTEF-1 flox/flox transgenic mice, RTEF-1 EC-specific knockout mice, show a significant decrease decrease in IGFBP-1 mRNA levels compared with controls (0.21 ± 0.09 vs. 1.0, respectively), while VE-Cadherin/RTEF-1 overexpressing transgenic mice have increased IGFBP-1 mRNA levels (25.4 ± 0.02-fold). Increased IGFBP-1 levels relate physiologically in our RTEF-1 EC-specific knockout by showing decreased blood glucose tolerance as well as increased insulin resistance as calculated by HOMA-IR compared with littermate controls, (4.1 ± 0.5 vs. 1.1 ± 0.2, respectively). Furthermore, the RTEF-1 EC-specific knockout mice showed a significant increase in systolic blood pressure (10mmHg ± 6mmHg) compared with littermate controls. Conclusion: These results demonstrate that RTEF-1-stimulated IGFBP-1 expression may be central to the mechanism by which RTEF-1 attenuates blood glucose levels and potential cardiovascular function. These findings provide the basis for novel insights into transcriptional regulation of IGFBP-1 and contribute to understanding the role of vascular endothelial cells in metabolism.
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