title: miRNA-21 is dysregulated in response to vein grafting in multiple models and genetic ablation in mice attenuates neointima formation.
abstract: OBJECTIVE
  The long-term failure of autologous saphenous vein bypass grafts due to neointimal thickening is a major clinical burden. Identifying novel strategies to prevent neointimal thickening is important. Thus, this study aimed to identify microRNAs (miRNAs) that are dysregulated during neointimal formation and determine their pathophysiological relevance following miRNA manipulation.
  
  
  RESULTS
  We undertook a microarray approach to identify dysregulated miRNAs following engraftment in an interpositional porcine graft model. These profiling experiments identified a number of miRNAs which were dysregulated following engraftment. miR-21 levels were substantially elevated following engraftment and these results were confirmed by quantitative real-time PCR in mouse, pig, and human models of vein graft neointimal formation. Genetic ablation of miR-21 in mice or grafted veins dramatically reduced neointimal formation in a mouse model of vein grafting. Furthermore, pharmacological knockdown of miR-21 in human veins resulted in target gene de-repression and a significant reduction in neointimal formation.
  
  
  CONCLUSIONS
  This is the first report demonstrating that miR-21 plays a pathological role in vein graft failure. Furthermore, we also provided evidence that knockdown of miR-21 has therapeutic potential for the prevention of pathological vein graft remodelling.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: McDonald
authors.forename: Katie M
authors.initials: KM
authors.lastname: White
authors.forename: Junxi
authors.initials: J
authors.lastname: Wu
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cooley
authors.forename: Keith E
authors.initials: KE
authors.lastname: Robertson
authors.forename: Crawford A
authors.initials: CA
authors.lastname: Halliday
authors.forename: John D
authors.initials: JD
authors.lastname: McClure
authors.forename: Sheila
authors.initials: S
authors.lastname: Francis
authors.forename: Ruifaug
authors.initials: R
authors.lastname: Lu
authors.forename: Simon
authors.initials: S
authors.lastname: Kennedy
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: George
authors.forename: Song
authors.initials: S
authors.lastname: Wan
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
mesh_terms: D000818:Animals; D017536:Carotid Artery, Common / Q000378:metabolism; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D058426:Neointima / Q000235:genetics*; D012501:Saphenous Vein / Q000378:metabolism* / Q000637:transplantation; D013552:Swine; D058017:Vascular Grafting; D014684:Venae Cavae / Q000378:metabolism
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs
keywords: MicroRNA; Neointimal formation; Vascular remodelling; Vein graft failure