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

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.

Triptolide Attenuates Transplant Vasculopathy Through Multiple Pathways

“…The pathological features of transplant artery includes vascular inflammation, neointima formation and progressive luminal obstruction, which are consistent with the TV-related complications after solid organ transplantation, what's more, compared with solid organ transplants such as heart and kidney, aortic transplant has the advantages of relatively simple operation. Therefore, many teams have used aortic transplantation as a small animal model for studying TV (25,26). Our results provided strong evidence that triptolide significantly ameliorated pathological injury associated with TV through multiple pathways.…”

CD34+KLF4+ Stromal Stem Cells Contribute to Endometrial Regeneration and Repair

“…This approach identified well-known regulators of the endometrium such as progesterone receptor (PGR) and FOXO1, as well as GATA2 as a potential stromal regulator, and is essential for endometrial stromal cell differentiation in vitro ( Kin et al, 2015 ). Of note, GATA2 is a critical factor for vascular development and vascular remodeling in adults in our previous studies ( Qiu et al, 2017 ; Yu et al, 2010 ). However, how the vascular GATA2 + and perivascular CD146 + PDGFRβ + cells contribute to cyclic regeneration of the endometrium needs to be determined.…”

Quantitative and qualitative impairments in GATA2 and myeloid neoplasms

“…Analyses of GATA factors have clarified functional differences between the NF and CF domains at the cellular and molecular levels . The CF domain is indispensable for binding to the consensus GATA‐binding motif of target genes (Figure a) and for specific interactions with a range of proteins that modify the function of GATA factors through acetylation, phosphorylation, and sumoylation . For example, the histone acetyltransferases p300 and CBP interact with GATA factors through the CF domain and acetylate several lysine residues of GATA factors to activate the functions of the protein …”

“…32 The CF domain is indispensable for binding to the consensus GATA-binding motif of target genes (Figure 2a) and for specific interactions with a range of proteins that modify the function of GATA factors through acetylation, phosphorylation, and sumoylation. [33][34][35] For example, the histone acetyltransferases p300 and CBP interact with GATA factors through the CF domain and acetylate several lysine residues of GATA factors to activate the functions of the protein. 33,[36][37][38] Indeed, GATA factors are known to interact with many transcription factors, modulating the functions of both.…”