miR-223-3p Prevents Necroptotic Macrophage Death by Targeting Ripk3 in a Negative Feedback Loop and Consequently Ameliorates Advanced Atherosclerosis

坏死性下垂 基因剔除小鼠 程序性细胞死亡 细胞凋亡 癌症研究 细胞生物学 小RNA 下调和上调 生物 化学 受体 基因 生物化学
作者
Yunhui Jia,Lianping Cheng,Jianhua Yang,Jia-Qi Mao,Yizhao Xie,Xian‐Wen Yang,Xin Zhang,Dingxin Wang,Zengdian Zhao,Andreas Schober,Yuanyuan Wei
出处
期刊:Arteriosclerosis, Thrombosis, and Vascular Biology [Ovid Technologies (Wolters Kluwer)]
卷期号:44 (1): 218-237
标识
DOI:10.1161/atvbaha.123.319776
摘要

The formation of large necrotic cores results in vulnerable atherosclerotic plaques, which can lead to severe cardiovascular diseases. However, the specific regulatory mechanisms underlying the development of necrotic cores remain unclear.To evaluate how the modes of lesional cell death are reprogrammed during the development of atherosclerosis, the expression levels of key proteins that are involved in the necroptotic, apoptotic, and pyroptotic pathways were compared between different stages of plaques in humans and mice. Luciferase assays and loss-of-function studies were performed to identify the microRNA-mediated regulatory mechanism that protects foamy macrophages from necroptotic cell death. The role of this mechanism in atherosclerosis was determined by using a knockout mouse model with perivascular drug administration and tail vein injection of microRNA inhibitors in Apoe-/- mice.Here, we demonstrate that the necroptotic, rather than the apoptotic or pyroptotic, pathway is more activated in advanced unstable plaques compared with stable plaques in both humans and mice, which closely correlates with necrotic core formation. The upregulated expression of Ripk3 (receptor-interacting protein kinase 3) promotes the C/EBPβ (CCAAT/enhancer binding protein beta)-dependent transcription of the microRNA miR-223-3p, which conversely inhibits Ripk3 expression and forms a negative feedback loop to regulate the necroptosis of foamy macrophages. The knockout of the Mir223 gene in bone marrow cells accelerates atherosclerosis in Apoe-/- mice, but this effect can be rescued by Ripk3 deficiency or treatment with the necroptosis inhibitors necrostatin-1 and GSK-872. Like the Mir223 knockout, treating Apoe-/- mice with miR-223-3p inhibitors increases atherosclerosis.Our study suggests that miR-223-3p expression in macrophages protects against atherosclerotic plaque rupture by limiting the formation of necrotic cores, thus providing a potential microRNA therapeutic candidate for atherosclerosis.
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