TRIM9-Mediated Degradation of SMAD4 Promotes Pyroptosis and Disruption of the Endothelial Barrier in Aortic Dissection Disease.

Aortic dissection (AD) is a life-threatening cardiovascular disease with exceedingly high mortality, particularly during the acute phase. Ubiquitination modification is implicated in the pathogenesis of cardiovascular diseases through diverse biological processes. However, the role of TRIM9, an E3 ubiquitin ligase, in AD remains unexplored. In this study, the expression profiles of TRIM9 and SMAD4 were analyzed using clinical samples, as well as Angiotensin II (Ang II)-induced mouse and human aortic endothelial cell (HAEC) models. Endothelial barrier function in AD was assessed through CCK-8 assays, vascular permeability measurements, immunofluorescence staining, hematoxylin-eosin and Verhoeff's van Gieson staining, and Western blot analysis. The underlying molecular mechanisms were elucidated using quantitative real-time PCR, immunoprecipitation (IP), co-immunoprecipitation (Co-IP), and enzyme-linked immunosorbent assay (ELISA). TRIM9 was markedly overexpressed, whereas SMAD4 was significantly downregulated in AD. Knockdown of TRIM9 attenuated endothelial permeability, preserved the endothelial barrier integrity, and inhibited pyroptosis both in vivo and in vitro. Mechanistically, TRIM9 promoted the ubiquitination and subsequent proteasomal degradation of SMAD4, thereby exacerbating AD progression. Collectively, these findings demonstrate that elevated TRIM9 expression aggravates AD progression through SMAD4 destabilization, offering novel therapeutic insights for AD management.