Involvement of USP7 in aggravating Kawasaki disease by promoting TGFβ2 signaling mediated endothelial-mesenchymal transition and coronary artery remodeling.

Kawasaki disease (KD), characterized by systematic vasculitis, is a leading cause of pediatric heart disease. Although recent studies have highlighted the critical role of deubiquitinases in vascular pathophysiology, their specific contribution to KD remains largely unknown. Herein, we investigated the function of the deubiquitinase USP7 in both KD patients and a CAWS-induced KD murine model. USP7 expression level is increased both in HCAECs induced by KD sera and cardiac CD31 endothelial cells of KD mice. Whereas knockout of USP7 increases the cellular proportion of endothelial cells and potentially attenuates the elevated EndoMT, fibrosis, and inflammation in cardiac tissue of KD mice, consistently with the in vitro experiment observed in HCAECs induced by TGF-β2. Mechanistically, USP7 interacts with SMAD2/3, enhancing their protein stability by removing the K48 ubiquitin chain from both proteins and preventing their proteasome degradation, thus increasing the p-SMAD2 levels and nuclear entry. Importantly, intraperitoneal injection of USP7 inhibitor, P22077 elicited a robust anti-EndoMT and anti-vascular inflammation effect in KD model mice. Therefore, our study uncovered a previously unrecognized function of increased USP7 in KD by augmenting TGFβ2/SMAD2/SMAD3 signaling, thus facilitating the transcription of genes implicated in the EndoMT, cardiac fibrosis, and vascular remodeling. Our finding suggests that USP7 could serve as a potential therapeutic target for the prevention and treatment of coronary artery lesions in KD and related vascular diseases.