College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Nat Commun. 2017 Jun 1;8:15426. doi: 10.1038/ncomms15426.
Data from clinical research and our previous study have suggested the potential involvement of SENP1, the major protease of post-translational SUMOylation, in cardiovascular disorders. Here, we investigate the role of SENP1-mediated SUMOylation in graft arteriosclerosis (GA), the major cause of allograft failure. We observe an endothelial-specific induction of SENP1 and GATA2 in clinical graft rejection specimens that show endothelial activation-mediated vascular remodelling. In mouse aorta transplantation GA models, endothelial-specific SENP1 knockout grafts demonstrate limited neointima formation with attenuated leukocyte recruitment, resulting from diminished induction of adhesion molecules in the graft endothelium due to increased GATA2 SUMOylation. Mechanistically, inflammation-induced SENP1 promotes the deSUMOylation of GATA2 and IκBα in endothelial cells, resulting in increased GATA2 stability, promoter-binding capability and NF-κB activity, which leads to augmented endothelial activation and inflammation. Therefore, upon inflammation, endothelial SENP1-mediated SUMOylation drives GA by regulating the synergistic effect of GATA2 and NF-κB and consequent endothelial dysfunction.
来自临床研究和我们之前研究的数据表明，主要的 SUMO 化翻译后蛋白酶 SENP1 可能参与心血管疾病。在这里，我们研究了 SENP1 介导的 SUMO 化在移植物动脉硬化（GA）中的作用，GA 是同种异体移植失败的主要原因。我们观察到在临床移植物排斥标本中内皮特异性诱导 SENP1 和 GATA2，其显示内皮激活介导的血管重塑。在小鼠主动脉移植 GA 模型中，内皮特异性 SENP1 敲除移植物表现出有限的新生内膜形成，白细胞募集减少，这是由于由于 GATA2 的 SUMO 化增加，导致移植物内皮中粘附分子的诱导减少。从机制上讲，炎症诱导的 SENP1 促进内皮细胞中 GATA2 和 IκBα 的去 SUMO 化，导致 GATA2 稳定性、启动子结合能力和 NF-κB 活性增加，从而导致内皮激活和炎症增加。因此，在炎症时，内皮 SENP1 介导的 SUMO 化通过调节 GATA2 和 NF-κB 的协同作用以及随后的内皮功能障碍来驱动 GA。
