title: MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1.
abstract: Atherosclerotic plaque vulnerability is the major cause for acute stroke and could be regulated by macrophage polarization. MicroRNA-181b (miR-181b) was involved in macrophage differential. Here, we explore whether miR-181b could regulate atherosclerotic plaque vulnerability by modulating macrophage polarization and the underline mechanisms. In acute stroke patients with atherosclerotic plaque, we found that the serum level of miR-181b was decreased. Eight-week apolipoprotein E knockout (ApoE-/-) mice were randomly divided into three groups (N = 10): mice fed with normal saline (Ctrl), mice fed with high-fat diet, and tail vein injection with miRNA agomir negative control (AG-NC)/miR-181b agomir (181b-AG, a synthetic miR-181b agonist). We found that the serum level of miR-181b in AG-NC group was lower than that in Ctrl group. Moreover, 181b-AG could upregulate miR-181b expression, reduce artery burden and attenuate atherosclerotic plaque vulnerability by modulating macrophage polarization. In RAW264.7 cells treated with oxidized low-density lipoprotein (ox-LDL), we found miR-181b could reverse the function of ox-LDL on M1/M2 markers at both mRNA and protein levels. Furthermore, by employing luciferase reporter assay, we found that Notch1 was a direct target of miR-181b and could be regulated by miR-181b in vivo and in vitro. Finally, inhibition of Notch1 could abolish the function of downregulating miR-181b on increasing M2 phenotype macrophages. Our study demonstrates that administration of miR-181b could reduce atherosclerotic plaque vulnerability partially through modulating macrophage phenotype by directly targeting Notch1.
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Tian-Hui
authors.initials: TH
authors.lastname: An
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Quan-Wei
authors.initials: QW
authors.lastname: He
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Yuan-Peng
authors.initials: YP
authors.lastname: Xia
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Suraj
authors.initials: S
authors.lastname: Baral
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Jin
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Li
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Meng-Die
authors.initials: MD
authors.lastname: Wang
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
authors.affiliation: The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China. zhulq1979@gmail.com.|Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. zhulq1979@gmail.com.
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. hubo@mail.hust.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D059305:Diet, High-Fat; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000819:agonists* / Q000097:blood; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D035683:MicroRNAs; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C529100:mirn181 microRNA, mouse; C099252:oxidized low density lipoprotein
keywords: Atherosclerotic plaque vulnerability; Ischemic stroke; Macrophage polarization; Notch1; miR-181b