177 - USP7 promotes endothelial-mesenchymal transition and coronary artery remodeling by deubiquitinating and stabilizing SMAD2 and SMAD3 proteins in Kawasaki disease

Publication Number: 177.7007

Guanghui Qian, Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, Jiangsu, China (People's Republic)

Background: Kawasaki disease (KD) is a leading cause of pediatric heart disease and characterized by systematic vasculitis and coronary artery remodeling. The latter could be attributed to endothelial-to-mesenchymal transition (EndoMT). Although recent studies have highlighted a critical role of USP7 in regulating numerous cellular processes including transdifferentiation, whether USP7 modulates EndoMT leading to coronary artery remodeling in KD remains unknown.

Objective: This study aims to elucidate the role of the deubiquitinating enzyme USP7 in KD pathogenesis.

Design/Methods: These effects were identified using proteomic anayses, sera samples from KD children, single-cell RNA sequencing of murine cardiac tissue, Usp7 knockout mice models, and ubiquitin assays.

Results: Our findings indicate elevated levels of USP7, fibrosis, and TGFβ-mediated EndoMT in patients, cell lines, and KD mouse models. USP7 positively regulates TGFβ-mediated EndoMT, fibrosis, migration, and permeability in HCAECs. Mechanistically, USP7 interacts with SMAD2 and SMAD3, deubiquitinates SMAD2 at lysine residues 156 and 383 through K48-linked polyubiquitination, and influences TGFβ2-induced phosphorylation and nuclear translocation of SMAD2. Furthermore, USP7 inhibition causes a significant increase in the proportion of endothelial cells and a concomitant decrease in the percentage of fibroblasts within the cardiac tissue of KD mice. Knockout of USP7 or using its inhibitor substantially alleviates immune cell infiltration, EndoMT, and fibrosis in vitro and in vivo.

Conclusion(s): Our study thus provides evidence that USP7 exacerbates the progression of inflammation, EndoMT, and cardiac fibrosis in KD, underscoring the potential for developing USP7-targeting therapeutics for systemic vasculitis in KD.