RTEF-1, an Upstream Gene of Hypoxia-inducible Factor-1α, Accelerates Recovery from Ischemia*

The amount of available hypoxia-inducible factor (HIF)-1α has been considered to be largely a consequence of post-translational modification by multiple ubiquitin-proteasome pathways. However, the role of transcriptional regulation of HIF-1α is less certain, and the mechanisms of transcriptional regulation of HIF-1α require further investigation. Here we report that related transcriptional enhancer factor-1 (RTEF-1), a member of the TEF transcriptional factor family, transcriptionally regulates the HIF-1α gene under normoxic and hypoxic conditions. The expression of HIF-1α mRNA was decreased in endothelial cells in which RTEF-1 was knocked down with siRNA. Sequential deletional analysis of the HIF-1α promoter revealed that the MCAT-like element in the HIF-1α promoter was essential for HIF-1α transcription. Binding of RTEF-1 to the MCAT-like element was confirmed by ChIP. Treatment of endothelial cells with a HIF-1 inhibitor resulted in retardation of RTEF-1-induced proliferation and tube formation. Moreover, increased HIF-1α expression was observed in transgenic mice expressing RTEF-1 under the VE-cadherin promoter (VE-Cad/RTEF-1). VE-Cad/RTEF-1 mice subjected to hindlimb ischemia demonstrated increased levels of HIF-1α, accelerated recovery of blood flow, and increased capillary density compared with littermate controls. These results identify RTEF-1 as a regulator of HIF-1α transcription, which results in up-regulation of HIF-1α and acceleration of recovery from ischemia.