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

Cong Qiu, Yuewen Wang, Haige Zhao, Lingfeng Qin, Yanna Shi, Xiaolong Zhu, Lin Song, Xiaofei Zhou, Jian Chen, Hong Zhou, Haifeng Zhang, George Tellides, Wang Min and Luyang Yu ()
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Cong Qiu: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Yuewen Wang: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Haige Zhao: First Affiliated Hospital, School of Medicine, Zhejiang University
Lingfeng Qin: Yale University School of Medicine
Yanna Shi: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Xiaolong Zhu: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Lin Song: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Xiaofei Zhou: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Jian Chen: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Hong Zhou: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University
Haifeng Zhang: Yale University School of Medicine
George Tellides: Yale University School of Medicine
Wang Min: Yale University School of Medicine
Luyang Yu: College of Life Sciences, Institute of Genetics and Regenerative Biology, Zhejiang University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15426

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