Differential but Complementary HIF1α and HIF2α Transcriptional Regulation
Differential but Complementary HIF1α and HIF2α Transcriptional Regulation
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DOI：
10.1016/j.ymthe.2018.05.004
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发表时间：
2018-07-05
影响因子：
12.4
通讯作者：
Yla-Herttuala, Seppo
中科院分区：
文献类型：
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作者：
Downes, Nicholas L.;Laham-Karam, Nihay;Yla-Herttuala, Seppo
有效的血管再生可以为多种病理提供治疗益处，特别是在慢性外周动脉疾病（PAD）和心肌缺血中。缺氧诱导因子（HIF）介导细胞对缺氧的转录反应，并调节血管生成所需的多个过程，以最终恢复灌注和氧气供应。在内皮细胞中，已知HIF 1 α和HIF 2 α都有助于这种作用;然而，这些HIF α中的每一个的程度和个体作用仍不清楚。为了表征HIF α的个体作用，我们对稳定形式的HIF 1 α和HIF 2 α的转录产物进行了测序，它们分别调节701和1，454个基因。HIF 1 α转录主要调节代谢重编程，而HIF 2 α在调节血管生成细胞外信号传导、引导信号和细胞外基质重塑因子方面发挥更大作用。此外，HIF 2 alpha几乎专门调节大量不同的转录因子和辅调节因子子集，这些转录因子和辅调节因子促成了其在缺氧中的不同作用。进一步了解HIF如何调节缺氧和血管生成中的细胞过程，可以提供新的途径来调节生理性血管生成，以增强缺血性疾病和其他病理条件下的血管重建。
Effective vascular regeneration could provide therapeutic benefit for multiple pathologies, especially in chronic peripheral artery disease (PAD) and myocardial ischemia. The hypoxia inducible factors (HIFs) mediate the cellular transcriptional response to hypoxia and regulate multiple processes that are required for angiogenesis to ultimately restore perfusion and oxygen supply. In endothelial cells, both HIF1 alpha and HIF2 alpha are known to contribute to this role; however, the extent and individual roles of each of these HIF alpha remain unclear. To characterize the individual roles of HIF alpha, we sequenced the transcriptional outputs of stabilized forms of HIF1 alpha and HIF2 alpha, where they regulated 701 and 1,454 genes, respectively. HIF1 alpha transcription primarily regulated metabolic reprogramming, whereas HIF2 alpha exerted a larger role in regulating angiogenic extracellular signaling, guidance cues, and extracellular matrix remodeling factors. Furthermore, HIF2 alpha almost exclusively regulated a large and diverse subset of transcription factors and coregulators that contribute to its diverse roles in hypoxia. Further understanding of how HIFs regulate cellular processes in hypoxia and angiogenesis could offer new avenues to modulate physiological angiogenesis to enhance revascular-isation in ischemic conditions and other pathologies.