Kim Eun-Jin, Yoo Young-Gun, Yang Woo-Kyeom, Lim Young-Soun, Na Tae-Young, Lee In-Kyu, Lee Mi-Ock
College of Pharmacy and Bio-MAX Institute, Seoul National University, Seoul, Korea.
Arterioscler Thromb Vasc Biol. 2008 Oct;28(10):1796-802. doi: 10.1161/ATVBAHA.108.171546. Epub 2008 Jul 24.
Hypoxia-inducible factor 1alpha (HIF-1alpha) 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 (RORalpha) have been implicated in cardiovascular diseases such as atherosclerosis. In this study, we have investigated the potential roles of RORalpha in the hypoxia signaling pathway in connection with activation of HIF-1alpha.
Under hypoxic conditions, expression of RORalpha was induced. When RORalpha was introduced exogenously, protein level as well as transcriptional activity of HIF-1alpha was enhanced. Putative ligands of RORalpha, such as melatonin and cholesterol sulfate, induced transcriptional activity for HIF-1alpha, which was abolished by RNA interference against RORalpha. RORalpha was physically associated with HIF-1alpha through DNA binding domain, which was required to the RORalpha-induced stabilization and transcriptional activation of HIF-1alpha. Finally, either infection with adenovirus encoding RORalpha or treatment with ROR ligands enhanced the formation of capillary tubes by human umbilical vascular endothelial cells.
Our results provide a new insight for the function of RORalpha in amplification of hypoxia signaling and suggest a potential application of RORalpha ligands for the therapy of hypoxia-associated vascular diseases.
缺氧诱导因子1α（HIF-1α）主要参与细胞对氧水平变化的适应过程，这对正常血管功能至关重要。最近，维甲酸相关孤儿受体α（RORα）的生理作用已被证实与动脉粥样硬化等心血管疾病有关。在本研究中，我们研究了RORα在与HIF-1α激活相关的缺氧信号通路中的潜在作用。
在缺氧条件下，RORα的表达被诱导。当外源性导入RORα时，HIF-1α的蛋白水平以及转录活性均增强。RORα的假定配体，如褪黑素和硫酸胆固醇，可诱导HIF-1α的转录活性，而针对RORα的RNA干扰可消除这种活性。RORα通过DNA结合结构域与HIF-1α发生物理相互作用，这是RORα诱导HIF-1α稳定和转录激活所必需的。最后，感染编码RORα的腺病毒或用ROR配体处理均可增强人脐静脉血管内皮细胞的毛细血管管腔形成。
我们的结果为RORα在缺氧信号放大中的功能提供了新的见解，并提示RORα配体在缺氧相关血管疾病治疗中的潜在应用。
