Molecular medicine (Cambridge, Mass.) · 2025
Ubiquitin-specific protease 38 modulates atrial fibrillation susceptibility in chronic kidney disease via STRAP stabilization and activation of TGF-β/SMAD signaling.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Meng Hong, Qu Zongze, Xiao Zheng, Kong Bin, Yang Hongjie, Shuai Wei, Huang He
Аннотация
OBJECTIVE: This study aimed to elucidate the role of the deubiquitinase USP38 in chronic kidney disease (CKD)-associated atrial fibrillation (AF) by investigating its impact on atrial structural and electrical remodeling and its interaction with STRAP and TGF-β/SMAD signaling.
METHODS: A murine CKD model was established using a two-stage 5/6 nephrectomy. Cardiomyocyte-specific USP38 knockout (USP38-CKO) and overexpression (USP38-TG) mice were generated. Atrial remodeling, electrophysiological parameters, and fibrosis markers were assessed by echocardiography, histology, and immunoblotting. In parallel, HL-1 cells were treated with indoxyl sulfate (100 μM) and subjected to adenoviral-mediated USP38 modulation. Molecular interactions between USP38 and STRAP were evaluated using immunofluorescence, co-immunoprecipitation, and ubiquitination assays. STRAP knockdown studies further validated the downstream effects of USP38.
RESULTS: CKD induced significant upregulation of USP38 in atrial tissue and HL-1 cells. USP38-CKO attenuated atrial fibrosis and reduced collagen I/III and α-SMA expression, whereas USP38-TG exacerbated these effects. Notably, USP38 modulation did not significantly alter atrial effective refractory period, suggesting its primary involvement in structural rather than direct electrical remodeling. Mechanistic studies revealed that USP38 stabilizes STRAP via deubiquitination, thereby enhancing TGF-β/SMAD signaling. STRAP knockdown reversed the pro-fibrotic and arrhythmogenic effects induced by USP38 overexpression.
CONCLUSION: USP38 is a critical mediator of CKD-associated AF, promoting atrial fibrosis and electrical remodeling via STRAP stabilization and TGF-β/SMAD pathway activation. Targeting USP38 may represent a novel therapeutic strategy for CKD-associated AF.
METHODS: A murine CKD model was established using a two-stage 5/6 nephrectomy. Cardiomyocyte-specific USP38 knockout (USP38-CKO) and overexpression (USP38-TG) mice were generated. Atrial remodeling, electrophysiological parameters, and fibrosis markers were assessed by echocardiography, histology, and immunoblotting. In parallel, HL-1 cells were treated with indoxyl sulfate (100 μM) and subjected to adenoviral-mediated USP38 modulation. Molecular interactions between USP38 and STRAP were evaluated using immunofluorescence, co-immunoprecipitation, and ubiquitination assays. STRAP knockdown studies further validated the downstream effects of USP38.
RESULTS: CKD induced significant upregulation of USP38 in atrial tissue and HL-1 cells. USP38-CKO attenuated atrial fibrosis and reduced collagen I/III and α-SMA expression, whereas USP38-TG exacerbated these effects. Notably, USP38 modulation did not significantly alter atrial effective refractory period, suggesting its primary involvement in structural rather than direct electrical remodeling. Mechanistic studies revealed that USP38 stabilizes STRAP via deubiquitination, thereby enhancing TGF-β/SMAD signaling. STRAP knockdown reversed the pro-fibrotic and arrhythmogenic effects induced by USP38 overexpression.
CONCLUSION: USP38 is a critical mediator of CKD-associated AF, promoting atrial fibrosis and electrical remodeling via STRAP stabilization and TGF-β/SMAD pathway activation. Targeting USP38 may represent a novel therapeutic strategy for CKD-associated AF.