Nrf2 transcriptional upregulation of IDH2 to tune mitochondrial dynamics and rescue angiogenic function of diabetic EPCs

作者：Xiaozhen Dai, Kai Wang, Jiawei Fan, Hanjie Liu, Fan Xia, Qian Lin, Yuhang Chen, Hu Chen, Yao Li, Hairong Liu, Oscar Chen, Jing Chen, Xiaohong Li, Di Ren, Ji Li, Daniel J. Conklin, Kupper A. Wintergerst, Yu Li, Lu Cai, Zhongbin Deng, Xiaoqing Yan, Yi Tan · 发表于：Redox Biology · 年份：2022 · DOI：10.1016/j.redox.2022.102449 · 被引用次数：64 · 研究领域：Angiogenesis and VEGF in Cancer、Eicosanoids and Hypertension Pharmacology、Cancer, Hypoxia, and Metabolism

Endothelial progenitor cells (EPCs) are reduced in number and impaired in function in diabetic patients. Whether and how Nrf2 regulates the function of diabetic EPCs remains unclear. In this study, we found that the expression of Nrf2 and its downstream genes were decreased in EPCs from both diabetic patients and db/db mice. Survival ability and angiogenic function of EPCs from diabetic patients and db/db mice also were impaired. Gain- and loss-of-function studies, respectively, showed that knockdown of Nrf2 increased apoptosis and impaired tube formation in EPCs from healthy donors and wild-type mice, while Nrf2 overexpression decreased apoptosis and rescued tube formation in EPCs from diabetic patients and db/db mice. Additionally, proangiogenic function of Nrf2-manipulated mouse EPCs was validated in db/db mice with hind limb ischemia. Mechanistic studies demonstrated that diabetes induced mitochondrial fragmentation and dysfunction of EPCs by dysregulating the abundance of proteins controlling mitochondrial dynamics; upregulating Nrf2 expression attenuated diabetes-induced mitochondrial fragmentation and dysfunction and rectified the abundance of proteins controlling mitochondrial dynamics. Further RNA-sequencing analysis demonstrated that Nrf2 specifically upregulated the transcription of isocitrate dehydrogenase 2 (IDH2), a key enzyme regulating tricarboxylic acid cycle and mitochondrial function. Overexpression of IDH2 rectified Nrf2 knockdown- or diabetes-induced mito...