title: MiR-29b Downregulation Induces Phenotypic Modulation of Vascular Smooth Muscle Cells: Implication for Intracranial Aneurysm Formation and Progression to Rupture.
abstract: OBJECTIVE
  Our previous microarray results identified numerous microRNAs (miRNAs), including miR-29b, that were differentially expressed in the serum of intracranial aneurysm (IA) patients. The current study aimed to investigate whether miR-29b downregulation in IA could promote the phenotypic modulation of vascular smooth muscle cells (VSMCs) involved in the pathogenesis of aneurysm by activating ATG14-mediated autophagy.
  
  
  METHODS
  First, the levels of miR-29b and autophagy related genes (ATGs) between IA patients and normal subjects were compared. Next, we modified the level of miR-29b via lentivirus particles in the VSMCs and examined the effects of miR-29b on proliferation, migration, and phenotypic modulation of VSMCs from a contractile phenotype to a synthetic phenotype, as well as the levels of autophagy. Finally, the binding of miR-29b to the 3'UTR of ATG14 mRNA and its effects on ATG14 expression were analysed by a luciferase reporter assay and Western blot, respectively.
  
  
  RESULTS
  The level of miR-29b was decreased, and autophagy markers were increased in the IA patients compared to that of the normal subjects. Knockdown of miR-29b significantly promoted VSMCs proliferation and migration and, more importantly, induced the phenotypic modulation associated with autophagy activation, whereas miR-29b overexpression showed the opposite effects. The luciferase reporter assay demonstrated that ATG14 was a functional target gene of miR-29b. Notably, knockdown of ATG14 by siRNA apparently abrogated miR-29b inhibition-mediated phenotypic modulation.
  
  
  CONCLUSIONS
  Downregulation of miR-29b induced VSMCs phenotypic modulation by directly activating ATG14-mediated autophagy, which is associated with the formation, growth and rupture of IAs.
authors.forename: Liqian
authors.initials: L
authors.lastname: Sun
authors.forename: Manman
authors.initials: M
authors.lastname: Zhao
authors.forename: Jingbo
authors.initials: J
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Lv
authors.forename: Youxiang
authors.initials: Y
authors.lastname: Li
authors.forename: Xinjian
authors.initials: X
authors.lastname: Yang
authors.forename: Aihua
authors.initials: A
authors.lastname: Liu
authors.forename: Zhongxue
authors.initials: Z
authors.lastname: Wu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000070416:Antagomirs / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D000071183:Autophagy-Related Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D055815:Young Adult
chemical_list: C539000:ATG14 protein, human; C502778:ATG5 protein, human; D033942:Adaptor Proteins, Vesicular Transport; D000070416:Antagomirs; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D035683:MicroRNAs; D034741:RNA, Small Interfering
keywords: ATG14; Autophagy; Intracranial aneurysm; MiR-29b; Phenotypic modulation; Vascular smooth muscle cell