miR-223-3p Prevents Necroptotic Macrophage Death by Targeting Ripk3 in a Negative Feedback Loop and Consequently Ameliorates Advanced Atherosclerosis
miR-223-3p Prevents Necroptotic Macrophage Death by Targeting Ripk3 in a Negative Feedback Loop and Consequently Ameliorates Advanced Atherosclerosis
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DOI：
10.1161/atvbaha.123.319776
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发表时间：
2023-11
期刊：
影响因子：
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通讯作者：
Yunhui Jia;Lianping Cheng;Jiaxuan Yang;Jiaqi Mao;Yuhuai Xie;Xian Yang;Xin Zhang;Dingxin Wang;Zhen Zhao;Andreas Schober;Yuanyuan Wei
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文献类型：
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作者：
Yunhui Jia;Lianping Cheng;Jiaxuan Yang;Jiaqi Mao;Yuhuai Xie;Xian Yang;Xin Zhang;Dingxin Wang;Zhen Zhao;Andreas Schober;Yuanyuan Wei
背景：大坏死核心的形成导致易损的动脉粥样硬化斑块，可导致严重的心血管疾病。然而，坏死核形成的具体调控机制尚不清楚。方法：为了评估在动脉粥样硬化的发展过程中病变细胞死亡的模式是如何被重新编程的，我们比较了人类和小鼠斑块不同阶段中涉及坏死性坏死、凋亡和焦亡途径的关键蛋白的表达水平。荧光素酶测定和功能丧失研究，以确定微rna介导的调节机制，保护泡沫巨噬细胞免于坏死细胞死亡。在Apoe−/−小鼠中，通过血管周围给药和尾静脉注射microRNA抑制剂的敲除小鼠模型来确定这一机制在动脉粥样硬化中的作用。结果：在这里，我们证明，与人类和小鼠的稳定斑块相比，晚期不稳定斑块中的坏死坏死途径比凋亡或焦亡途径更活跃，这与坏死核心的形成密切相关。Ripk3（受体相互作用蛋白激酶3）的上调表达可促进microRNA miR-223-3p的C/EBPβ （CCAAT/增强子结合蛋白β）依赖性转录，反过来抑制Ripk3的表达，形成负反馈回路调节泡沫巨噬细胞的坏死。敲除骨髓细胞中的Mir223基因会加速Apoe−/−小鼠的动脉粥样硬化，但这种效应可以通过Ripk3缺失或用坏死性坏死抑制剂necrostatin-1和GSK-872治疗来恢复。与Mir223敲除一样，用miR-223-3p抑制剂治疗Apoe−/−小鼠会增加动脉粥样硬化。结论：我们的研究表明，巨噬细胞中miR-223-3p的表达通过限制坏死核心的形成来防止动脉粥样硬化斑块破裂，从而为动脉粥样硬化提供了潜在的microRNA治疗候选者。
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.