title: MicroRNA-33 protects against neointimal hyperplasia induced by arterial mechanical stretch in the grafted vein.
abstract: OBJECTIVE
  Mechanical factors play significant roles in neointimal hyperplasia after vein grafting, but the mechanisms are not fully understood. Here, we investigated the roles of microRNA-33 (miR-33) in neointimal hyperplasia induced by arterial mechanical stretch after vein grafting.
  
  
  RESULTS
  Grafted veins were generated by the 'cuff' technique. Neointimal hyperplasia and cell proliferation was significantly increased, and miR-33 expression was decreased after 1-, 2-, and 4-week grafts. In contrast, the expression of bone morphogenetic protein 3 (BMP3), which is a putative target of miR-33, and the phosphorylation of smad2 and smad5, which are potential downstream targets of BMP3, were increased in the grafted veins. miR-33 mimics/inhibitor and dual luciferase reporter assay confirmed the interaction of miR-33 and BMP3. miR-33 mimics attenuated, while miR-33 inhibitor accelerated, proliferation of venous smooth muscle cells (SMCs). Moreover, recombinant BMP3 increased SMC proliferation and P-smad2 and P-smad5 levels, whereas BMP3-directed siRNAs had the opposite effect. Then, venous SMCs were exposed to a 10%-1.25 Hz cyclic stretch (arterial stretch) by using the FX4000 cyclic stretch loading system in vitro to mimic arterial mechanical conditions. The arterial stretch increased venous SMC proliferation and repressed miR-33 expression, but enhanced BMP3 expression and smad2 and smad5 phosphorylation. Furthermore, perivascular multi-point injection in vivo demonstrated that agomiR-33 not only attenuates BMP3 expression and smad2 and smad5 phosphorylation, but also slows neointimal formation and cell proliferation in grafted veins. These effects of agomiR-33 on grafted veins could be reversed by local injection of BMP3 lentivirus.
  
  
  CONCLUSIONS
  The miR-33-BMP3-smad signalling pathway protects against venous SMC proliferation in response to the arterial stretch. miR-33 is a target that attenuates neointimal hyperplasia in grafted vessels and may have potential clinical applications.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Han
authors.initials: H
authors.lastname: Bao
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Yan
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Qing-Ping
authors.initials: QP
authors.lastname: Yao
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Xiao-Hu
authors.initials: XH
authors.lastname: Chen
authors.forename: Kai-Xuan
authors.initials: KX
authors.lastname: Wang
authors.forename: Bao-Rong
authors.initials: BR
authors.lastname: Shen
authors.forename: Ying-Xin
authors.initials: YX
authors.lastname: Qi
authors.forename: Zong-Lai
authors.initials: ZL
authors.lastname: Jiang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000070416:Antagomirs / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D055398:Bone Morphogenetic Protein 3 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D006965:Hyperplasia; D007601:Jugular Veins / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation*; D008297:Male; D040542:Mechanotransduction, Cellular; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D058426:Neointima; D010766:Phosphorylation; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D051899:Smad2 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D000070416:Antagomirs; C525759:Bmp3 protein, rat; D055398:Bone Morphogenetic Protein 3; C580642:MIRN33 microRNA, rat; D035683:MicroRNAs; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051902:Smad5 Protein; C497799:Smad5 protein, rat
keywords: Mechanical stretch; MicroRNAs; Neointimal hyperplasia; Smooth muscle cells; Vein graft