Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension

作者：Xiaofei Zhou, Yuan‐Qing Jiang, Yuewen Wang, Linge Fan, Yunhui Zhu, Yefeng Chen, Yiran Wang, Yingyi Zhu, Hongkun Wang, Zihang Pan, Zhoubin Li, Xiaolong Zhu, Ruizhe Ren, Zhen Ge, Dongwu Lai, En Yin Lai, Ting Chen, Kai Wang, Ping Liang, Lingfeng Qin, Cuiqing Liu, Cong Qiu, Michael Simons, Luyang Yu · 发表于：Circulation Research · 年份：2023 · DOI：10.1161/circresaha.122.321200 · 被引用次数：48 · 研究领域：Pulmonary Hypertension Research and Treatments、Mitochondrial Function and Pathology、Ubiquitin and proteasome pathways

BACKGROUND: Hypoxia is a major cause and promoter of pulmonary hypertension (PH), a representative vascular remodeling disease with poor prognosis and high mortality. However, the mechanism underlying how pulmonary arterial system responds to hypoxic stress during PH remains unclear. Endothelial mitochondria are considered signaling organelles on oxygen tension. Results from previous clinical research and our studies suggested a potential role of posttranslational SUMOylation (small ubiquitin-like modifier modification) in endothelial mitochondria in hypoxia-related vasculopathy. METHODS: Chronic hypoxia mouse model and Sugen/hypoxia rat model were employed as PH animal models. Mitochondrial morphology and subcellular structure were determined by transmission electron and immunofluorescent microscopies. Mitochondrial metabolism was determined by mitochondrial oxygen consumption rate and extracellular acidification rate. SUMOylation and protein interaction were determined by immunoprecipitation. RESULTS: The involvement of SENP1 (sentrin-specific protease 1)-mediated SUMOylation in mitochondrial remodeling in the pulmonary endothelium was identified in clinical specimens of hypoxia-related PH and was verified in human pulmonary artery endothelial cells under hypoxia. Further analyses in clinical specimens, hypoxic rat and mouse PH models, and human pulmonary artery endothelial cells and human embryonic stem cell-derived endothelial cells revealed that short-term hypoxia-induce...