Inhibition of Abdominal Aortic Aneurysm Progression Through the CXCL12/CXCR4 Axis via MiR206-3p Sponge
Xuezhen Xuan1, Yaling Li1, Genmao Cao1
1Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China.
Abstract:
Notably, the C-X-C Motif Chemokine Ligand 12/C-X-C Chemokine Receptor Type 4 (CXCL12/CXCR4) signalling pathway's activation is markedly increased in a mouse model of abdominal aortic aneurysms (AAA). Nonetheless, the precise contribution of this pathway to AAA development remains to be elucidated. The AAA mouse model was induced by local incubation with elastase and oral administration of β-aminopropionitrile. The activity level of the CXCL12/CXCR4 axis was evaluated in both human AAA patients and the mouse model. Smooth muscle cell lineage tracing determined the expression and localisation of CXCR4 in normal aorta and AAA tissue. By transfecting the MiR206-3p sponge to reduce the level of MiR206-3p in AAA, the effects of the CXCL12/CXCR4 pathway on AAA progression as well as the apoptosis and phenotypic transformation of vascular smooth muscle cells (VSMCs) were studied in vivo and in vitro. Single-cell RNA sequencing analysis, serum ELISA, and in vivo experiments indicate a pronounced activation of the CXCL12/CXCR4 axis in both AAA patients and the mouse model. Specific blocking of the CXCL12/CXCR4 axis significantly inhibited further expansion and rupture of the abdominal aorta and reduced the infiltration of inflammatory cells in the aorta and inhibited the phenotypic transformation of contractile VSMCs into a macrophage-like state. 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 signalling pathway.
Insights
The CXCL12/CXCR4 pathway significantly contributes to abdominal aortic aneurysms (AAA) development and rupture. Suppressing this pathway, particularly using a MiR206-3p sponge, offers a novel therapeutic strategy for AAA.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Vascular Biology
Background:
- Abdominal aortic aneurysms (AAA) are associated with increased activation of the C-X-C Motif Chemokine Ligand 12/C-X-C Chemokine Receptor Type 4 (CXCL12/CXCR4) signaling pathway.
- The exact role of this pathway in AAA pathogenesis requires further investigation.
Purpose of the Study:
- To elucidate the specific contribution of the CXCL12/CXCR4 axis to AAA development and progression.
- To evaluate the therapeutic potential of targeting the CXCL12/CXCR4 pathway in AAA.
Main Methods:
- Utilized a mouse model of AAA induced by elastase and beta-aminopropionitrile.
- Assessed CXCL12/CXCR4 axis activity in human AAA patients and the mouse model.
- Employed smooth muscle cell lineage tracing, MiR206-3p sponge transfection, in vivo/in vitro studies, single-cell RNA sequencing, and ELISA.
Main Results:
- Demonstrated pronounced activation of the CXCL12/CXCR4 axis in both human AAA and the mouse model.
- Showed that blocking the CXCL12/CXCR4 axis significantly reduced aortic expansion, rupture, and inflammatory cell infiltration.
- Observed inhibition of vascular smooth muscle cell (VSMC) phenotypic transformation into a macrophage-like state upon CXCL12/CXCR4 axis blockade.
Conclusions:
- The CXCL12/CXCR4 signaling pathway plays a critical role in AAA progression and rupture.
- Targeting the CXCL12/CXCR4 axis, potentially via a MiR206-3p sponge, is a promising therapeutic strategy to mitigate AAA development and rupture risk.
