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      Inhibition of polycomb repressor complex 2 ameliorates neointimal hyperplasia by suppressing trimethylation of H3K27 in vascular smooth muscle cells

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          Abstract

          Background and Purpose

          The increased proliferation and migration of vascular smooth muscle cells (VSMCs) after arterial injury contributes greatly to the pathogenesis of neointimal hyperplasia. As a major component of epigenetics, histone methylation plays an important role in several cardiovascular diseases. However, its role in restenosis is still unclear.

          Experimental Approach

          Human aortic VSMCs were challenged with PDGF‐BB, and total histones were extracted and analysed by HPLC/MS. For the in vivo study, rats were subjected to wire‐guided common carotid injury.

          Key Results

          PDGF‐BB markedly increased the H3K27me3 level, as demonstrated by use of HPLC/MS and confirmed by western blot analysis. Enhancer of zeste homologue 2 (EZH2), the histone H3K27 methyltransferase component of polycomb repressive complex 2, was also up‐regulated by PDGF‐BB in VSMCs, and in the neointimal hyperplasia induced by wire injury of the rat carotid artery. Furthermore, inhibiting H3K27me3 by treatment with 3‐μM UNC1999, an EZH2/1 inhibitor, significantly suppressed PDGF‐BB‐induced VSMC proliferation compared with the PDGF‐BB‐treated group. Consistently, neointimal formation was significantly attenuated by oral or perivascular administration of UNC1999 compared with the sham group. Mechanistically, the increase in H3K27me3 inhibited the transcription of the cyclin‐dependent kinase inhibitor p16 INK4A and thus promoted VSMC proliferation.

          Conclusions and Implications

          Vascular injury elevated the expression of EZH2 and the downstream target H3K27me3, which suppressed p16 INK4A expression in VSMCs and promoted VSMC proliferation and neointimal hyperplasia. EZH2 inhibition might be a potential therapeutic target for restenosis.

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          Author and article information

          Contributors
          xuzhang@tmu.edu.cn
          wangchunjiong@tmu.edu.cn
          zhuyi@tmu.edu.cn
          Journal
          Br J Pharmacol
          Br. J. Pharmacol
          10.1111/(ISSN)1476-5381
          BPH
          British Journal of Pharmacology
          John Wiley and Sons Inc. (Hoboken )
          0007-1188
          1476-5381
          19 July 2019
          September 2019
          : 176
          : 17 ( doiID: 10.1111/bph.v176.17 )
          : 3206-3219
          Affiliations
          [ 1 ] Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, and Department of Physiology and Pathophysiology Tianjin Medical University Tianjin China
          [ 2 ] Department of Cell Biology Tianjin Medical University Tianjin China
          [ 3 ] Department of Pharmacology Tianjin Medical University Tianjin China
          [ 4 ] Department of Biochemistry and Molecular Biology Tianjin Medical University Tianjin China
          Author notes
          [*] [* ] Correspondence

          Yi Zhu, Chunjiong Wang, and Xu Zhang, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 30070, China.

          Email: zhuyi@ 123456tmu.edu.cn ; wangchunjiong@ 123456tmu.edu.cn ; xuzhang@ 123456tmu.edu.cn

          Author information
          https://orcid.org/0000-0001-7725-9166
          Article
          PMC6692584 PMC6692584 6692584 BPH14754 2018-BJP-1610-RP.R1
          10.1111/bph.14754
          6692584
          31162630
          c41edd51-6a47-477f-a085-177ab16dc455
          © 2019 The British Pharmacological Society
          History
          : 18 December 2018
          : 21 March 2019
          : 20 May 2019
          Page count
          Figures: 7, Tables: 0, Pages: 14, Words: 5735
          Funding
          Funded by: National Natural Science Foundation of China
          Award ID: 91539108
          Award ID: 81790621
          Award ID: 81770836
          Award ID: 81822006
          Award ID: 81730014
          Categories
          Research Paper
          Research Papers
          Custom metadata
          2.0
          bph14754
          September 2019
          Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:14.08.2019

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