Inhibition of Elastase induced Abdominal Aortic Aneurysm Progression through the CXCL12/CXCR4 Axis via MiR206 3p Sponge

Abstract Background Prior research has established a significant association between the progression of abdominal aortic aneurysms (AAA) and the apoptosis and phenotypic transformation of vascular smooth muscle cells (VSMCs). Notably, the CXCL12/CXCR4 signaling pathway's activation is markedly increased in a mouse model of AAA. Nonetheless, the precise contribution of this pathway to AAA development remains to be elucidated. Materials and Methods We utilized a single-cell sequencing dataset pertaining to AAA from the Gene Expression Omnibus database, employing the R package CellChat (v1.1.3) to analyze communication strength, signaling pathways, and modes of interaction among various VSMC phenotypes and immune cells. The activity level of the CXCL12/CXCR4 axis was evaluated in both human AAA patients and a mouse model. We examined the impact of CXCR4-specific inhibitors on AAA progression and the regulatory influence of MiR206-3p sponge on this axis. Results Single-cell RNA sequencing analysis revealed a significant upregulation of CXCL12/CXCR4 axis in AAA tissues. Further, Serum ELISA and in vivo experiments indicate a pronounced activation of the CXCL12/CXCR4 axis in both AAA patients and the elastase-induced AAA mouse model. CXCR4-specific inhibitors inhibited further expansion and rupture of the abdominal aorta and reduced the infiltration of macrophages in the aorta. Diminishing miR206-3p levels in VSMCs led to a decrease in CXCR4 expression within AAA tissues and a reduction in serum CXCL12 concentrations. Furthermore, transfecting VSMCs with miR206-3p sponge curtailed apoptosis and phenotypic transformation, markedly reducing AAA diameter and rupture frequency in mice. In vitro experiments corroborated that blocking the CXCL12/CXCR4 axis mitigated apoptosis and phenotypic transformation of VSMCs. Conclusion Our findings propose that MiR206-3p sponge represents an innovative therapeutic strategy to attenuate AAA progression and rupture risk, primarily through the suppression of the CXCL12/CXCR4 signaling pathway.