MicroRNA-146a Prevents AAA Development Through Repressing VSMC Inflammation

促炎细胞因子 下调和上调 炎症 平衡 内科学 医学 内分泌学 血管平滑肌 免疫学 信号转导 细胞 发病机制 癌症研究 主动脉
作者
Weipeng Hu,Yu‐Tsung Shih,Qin-Yu Wang,Chih-I Lee,Haoyue Ma,Qingyi Zhang,Yi-Ju Ko,Zeyu Cai,Jeng‐Jiann Chiu,Rong Qi
出处
期刊:Hypertension [Lippincott Williams & Wilkins]
卷期号:83 (1): 57-72
标识
DOI:10.1161/hypertensionaha.125.25133
摘要

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.
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