UCP1 prevents the formation of thoracic aortic aneurysms and dissection by inhibiting the TLR4/NLRP3/IL-1β signaling pathway and VSMC phenotype switching in mice.

Thoracic aortic aneurysms and dissection (TAAD) is a life-condition associated with high morbidity and mortality. Research has proven that inflammation contributes to the progression of TAAD. Mitochondrial uncoupling protein 1 (UCP1) can inhibit the release of inflammatory factors in perivascular adipose tissue (PVAT), regulate fat and inflammation, to confer vascular protection. However, whether UCP1 can ameliorate TAAD has not been clarified. In this study, aortas were harvested from organ donors and TAAD patients to explore the expression of UCP1 and Toll-like receptor 4 (TLR4)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/interleukin-1β (IL-1β) signaling pathway. Meanwhile, in vitro and in vivo models of TAAD were constructed to clarify the impact of UCP1 expression on VSMCs and TAAD. UCP1 expression was significantly downregulated and the TLR4/NLRP3/IL-1β signaling pathway was activated in TAAD in vivo. Moreover, UCP1 inhibited the migration, invasion, apoptosis, and phenotype switching of VSMCs in vitro. UCP1 significantly blocked the β-aminopropionitrile (BAPN)-induced TAAD formation and rupture in mice, suppressed aortic dilation, elastic fiber fragmentation, and apoptosis in the aorta. It also activated the TLR4/NLRP3/IL-1β signaling pathway to alleviate aortic inflammation and prevent the degradation of systolic phenotype proteins and phenotype switching of VSMCs. These effects suggest that UCP1 may inhibit TAAD formation by blocking the TLR4/NLRP3/IL-1β signaling pathway and VSMC phenotype switching.