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Nat Commun. 2017 Jun 1;8:15426. doi: 10.1038/ncomms15426.

The critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis.

Qiu C1,2, Wang Y1,2, Zhao H3, Qin L4,5, Shi Y1,2, Zhu X1,2, Song L1,2, Zhou X1,2, Chen J1, Zhou H1, Zhang H4,5, Tellides G4,5, Min W4,5,6, Yu L1,2.

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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.
Department of Cardiothoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Department of Pathology and Surgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
The First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen University, Guangzhou 510080, China.


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.

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