Decellularized adipose matrix hydrogel-based in situ delivery of antagomiR-150-5p for rat abdominal aortic aneurysm therapy

Abstract

Abdominal aortic aneurysm (AAA) is a progressive aortic disease featured by inflammation, vascular smooth muscle cells (VSMCs) depletion, and elastin degradation. MicroRNAs were related to AAA formation, which bring the approach for precise and targeted drug therapy for AAA. We developed a new strategy based on decellularized adipose matrix (DAM) hydrogel immobilized on the adventitia to release antagomiR-150-5p for preventing the AAA development. In this study, Cacl₂-induced and elastase-induced rat AAA models were established. We found that miR-150-5p was upregulated while Notch3 was downregulated in two rat AAA models. Then a mold was designed for shaping hydrogel for miR-150-5p delivery around the abdominal aorta. Interestingly, inhibition of miR-150-5p in AAA by local release of antagomiR-150-5p with DAM hydrogel significantly prevented aortic dilation and elastin degradation. Moreover, inflammatory cell infiltration, the expression of inflammatory cytokines (MCP-1, TNF-α, and NF-κB (p65)), and matrix metalloproteinases (MMP-2, MMP-9) were increased while Notch3 and α-SMA were decreased in rat AAA, which can be attenuated by antagomiR-150-5p treatment. In VSMCs with TNF-α stimulation, we further demonstrated that inhibition of miR-150-5p downregulated NF-κB (p65), MMP-2, and MMP-9 and upregulated elastin via Notch3. This work presents a translational potential strategy for AAA repair via DAM hydrogel sustained release of antagomiR-150-5p, and highlights the mechanism of miR-150-5p during AAA progression by regulating Notch3.