title: MicroRNA-145 targeted therapy reduces atherosclerosis.
abstract: BACKGROUND
  MicroRNA are essential posttranscriptional modulators of gene expression implicated in various chronic diseases. Because microRNA-145 is highly expressed in vascular smooth muscle cells (VSMC) and regulates VSMC fate and plasticity, we hypothesized that it may be a novel regulator of atherosclerosis and plaque stability.
  
  
  RESULTS
  Apolipoprotein E knockout mice (ApoE(-/-)) mice were treated with either a microRNA-145 lentivirus under the control of the smooth muscle cell (SMC)-specific promoter SM22α or a SM22α control lentivirus before commencing the Western diet for 12 weeks. The SMC-targeted microRNA-145 treatment markedly reduced plaque size in aortic sinuses, ascending aortas, and brachiocephalic arteries. It also significantly increased fibrous cap area, reduced necrotic core area, and increased plaque collagen content. Cellular plaque composition analyses revealed significantly less macrophages in ApoE(-/-) mice treated with the SMC-specific microRNA-145. These mice also demonstrated marked increases in calponin levels and α-smooth muscle actin-positive SMC areas in their atherosclerotic lesions. Furthermore, lentiviral delivery of microRNA-145 resulted in reduced KLF4 and elevated myocardin expression in aortas from ApoE(-/-) mice, consistent with an effect of microRNA-145 to promote a contractile phenotype in VSMC.
  
  
  CONCLUSIONS
  VSMC-specific overexpression of microRNA-145 is a novel in vivo therapeutic target to limit atherosclerotic plaque morphology and cellular composition, shifting the balance toward plaque stability vs plaque rupture.
authors.affiliation: Division of Cardiac Surgery, Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.forename: Praphulla C
authors.initials: PC
authors.lastname: Shukla
authors.forename: Nandini
authors.initials: N
authors.lastname: Gupta
authors.forename: Brent M
authors.initials: BM
authors.lastname: Steer
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Ingram
authors.forename: Milan
authors.initials: M
authors.lastname: Gupta
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002339:Carotid Arteries / Q000378:metabolism; D002478:Cells, Cultured; D004036:Diet, Atherogenic; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014161:Transduction, Genetic
chemical_list: D000199:Actins; D001057:Apolipoproteins E; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008055:Lipids; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; D011993:Recombinant Fusion Proteins; C544013:alpha-smooth muscle actin, mouse