Transcriptional activation of HIF-1 by RORα and its role in hypoxia signaling

Objective -Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is primarily involved in the adapting of cells to changes in oxygen levels, which is essential for normal vascular function. Recently, physiological roles for retinoic acid -related orphan receptor alpha (ROR alpha) have been implicated in cardiovascular diseases such as atherosclerosis. In this study, we have investigated the potential roles of ROR alpha in the hypoxia signaling pathway in connection with activation of HIF-1 alpha. Methods and Results -Under hypoxic conditions, expression of ROR alpha was induced. When ROR alpha was introduced exogenously, protein level as well as transcriptional activity of HIF-1 alpha was enhanced. Putative ligands of ROR alpha, such as melatonin and cholesterol sulfate, induced transcriptional activity for HIF-1 alpha, which was abolished by RNA interference against ROR alpha. ROR alpha was physically associated with HIF-1 alpha through DNA binding domain, which was required to the ROR alpha-induced stabilization and transcriptional activation of HIF-1 alpha. Finally, either infection with adenovirus encoding ROR alpha or treatment with ROR ligands enhanced the formation of capillary tubes by human umbilical vascular endothelial cells. Conclusions -Our results provide a new insight for the function of ROR alpha in amplification of hypoxia signaling and suggest a potential application of ROR alpha ligands for the therapy of hypoxia-associated vascular diseases.