MicroRNA-146a Prevents AAA Development Through Repressing VSMC Inflammation

BACKGROUND: Vascular smooth muscle cell (VSMC) homeostasis is critical for abdominal aortic aneurysms (AAA) development. MicroRNA 146a (miR-146a) has been reported significantly altered in AAA tissues and plasma of the patients. However, the role of miR-146a in VSMC homeostasis and its impact on AAA development remains unclear. METHODS: MiR-146a expression was evaluated in plasma and aortas of AngII (angiotensin II) and PPE (porcine pancreatic elastase)-induced AAA mouse models. By constructing ApoE-/-MiR-146a-/- double knockout mice, we evaluated the effect of miR-146a knockout on AAA progression. Furthermore, transcriptomics analysis was performed to identify the mechanisms of miR-146a on VSMC homeostasis. RESULTS: MiR-146a expression in VSMCs was increased in aneurysm tissues of patients with AAA and mouse models. MiR-146a knockout aggravated the incidence rate and severity of AAA in AngII-induced ApoE-/- mice. Transcriptomics analysis revealed that miR-146a regulates various biological processes, including inflammatory responses. In vitro, miR-146a mimic inhibited TNF (tumor necrosis factor) α-induced VSMC inflammation, apoptosis, and dedifferentiation. Mechanistically, miR-146a reduced interleukin-1 receptor-associated kinase-1 and TNF receptor-associated factor-6 levels and then downregulated nuclear factor kappa-B/NOD (Nucleotide-binding oligomerization domain)-like receptor protein-3 signaling pathway to suppress VSMC inflammation induced by TNFα. Moreover, local administration of miR-146a agomir to abdominal aortas could significantly inhibit the dilatation of AAA. CONCLUSIONS: MiR-146a prevents AAA formation and progression by maintaining VSMC homeostasis in the proinflammatory microenvironment. Upregulation of miR-146a in the aortas shows great potential as a new therapeutic strategy to limit AAA expansion and progression.