Ubiquitin-like modifier-activating enzyme 1 as a potential therapeutic target for aortic dissection.

Abstract

Aortic dissection (AD) is a life-threatening aortopathy with no specific pharmacological therapy. Ubiquitination, a highly orchestrated enzymatic cascade involving sequential E1-E2-E3 interactions, is suggested to contribute to the disease pathogenesis. However, the specific role of E1 enzymes in AD progression remains unknown. In this study, we analyzed the aortic transcriptional profiles of a human ascending dissection dataset (GSE52093) and identified ubiquitin-like modifier-activating enzyme 1 (UBA1) as a significantly up-regulated E1 enzyme in human AD. This finding was further corroborated by immunohistochemistry and RT-qPCR in a mouse model of AD induced by β-aminopropionitrile (BAPN). Treatment of TAK-243, a specific UBA1 inhibitor, prevented BAPN-induced AD formation in mice and attenuated aortic medial degeneration, as evidenced by decreased elastin fragmentation (evaluated by EVG scoring), reduced vascular smooth muscle cell loss (visualized by α-SMA immunohistochemistry), and less extracellular matrix degradation (indicated by diminished MMP2 and MMP9 expression in immunohistochemistry and RT-qPCR). Furthermore, TAK-243 treatment attenuated lesional macrophage accumulation and activation, as demonstrated by CD68 immunohistochemistry and RT-qPCR analysis of aortic pro-inflammatory cytokine expression. In vitro, UBA1 activation was observed in macrophages (RAW264.7 cells) treated with angiotensin II (AngII), and TAK-243 significantly reduced AngII-induced macrophage activation, at least partially through the inhibition of IκBα and NF-κB p65 phosphorylation. In conclusion, we demonstrate that UBA1 may facilitate AD progression by promoting macrophage activation via the NF-κB signaling pathway. These findings reveal a pathogenic role for the E1 enzyme UBA1 in AD and show a pharmacological potential of UBA1-targeted therapy against this disease.