Let-7b-5p protects against aortic dissection by inhibiting inflammatory vascular smooth muscle cell PANoptosis
H Lu, C Lu, C ShihAbstract
Background
Vascular smooth muscle cell (VSMC) loss is a hallmark of aortic dissection (AD) pathogenesis. Emerging evidence suggests that PANoptosis, a unique inflammatory cell death mechanism involving apoptosis, necroptosis, and pyroptosis, drives medial degeneration. While microRNAs are essential post-transcriptional regulators, the specific contribution of let-7b-5p to VSMC PANoptosis and AD pathogenesis remains poorly defined.
Purpose
This study aimed to investigate whether let-7b-5p protects aortic integrity by modulating PANoptotic signaling.
Methods
AD was induced in mice using β-aminopropionitrile fumarate (BAPN) and Angiotensin II (Ang II). To assess therapeutic efficacy, mice were administered subcutaneously with let-7b-5p mimics or negative controls. Survival rates, AD incidence, and vascular morphology (H&E, EVG staining) were evaluated. The expression of PANoptotic executioners (CASP3, NLRP3, and MLKL) was quantified in the aortic media.
Results
In murine AD models, let-7b-5p expression was significantly downregulated, correlating with a robust increase in CASP3, NLRP3, and MLKL within the medial layer. Restoration of let-7b-5p significantly improved animal survival and decreased AD incidence. Histological analysis revealed that let-7b-5p overexpression markedly attenuated elastic fiber breakage, pseudolumen formation, and inflammatory cell infiltration. Furthermore, let-7b-5p delivery effectively suppressed the activation of PANoptosis-related markers in the aortic wall, preserving the VSMC population and structural stability.
Conclusions
Our findings identify let-7b-5p as a novel protective regulator that safeguards the aorta by suppressing VSMC PANoptosis. These results suggest that targeting the let-7b-5p axis may offer a potent therapeutic strategy to limit pathological remodeling and preventing AD.Scheme