title: Progressive Aortic Dilation Is Regulated by miR-17-Associated miRNAs.
abstract: Patients with a bicuspid aortic valve (BAV) are at increased risk for progressive aortic dilation associated with extracellular matrix (ECM) degradation by matrix metalloproteinases (MMP). However, the mechanisms responsible for initiating this process are unknown. In the heart, MMP activity is regulated by micro-ribonucleic acid-17 (miR-17)-related downregulation of tissue inhibitors of metalloproteinases (TIMP); a similar process may exist in the aorta.
  
  
  
  This study sought to ascertain whether aortic matrix degradation in BAV patients progresses by miR-17-related miRNA regulation of TIMP-MMP.
  
  
  
  To eliminate confounding patient-related factors, severely dilated and less dilated aortic tissue samples were collected from 12 BAV patients. Gene and protein expression levels were evaluated in paired tissue samples from the same patient and were compared to aortic samples from 16 patients with aortas that appeared to be normal.
  
  
  
  Gene expression analyses confirmed increased expression of miR-17-related miRNAs in less dilated compared with severely dilated tissue from the same patient or normal aortic sample. TIMP-1, -2, and -3 were significantly decreased, and MMP2 activity was significantly increased in less dilated samples, suggesting that this normal-looking tissue was in the early stages of ECM degradation. Smooth muscle cells isolated from normal or BAV aortas transfected with an miR-17 mimic had decreased TIMP-1 and -2 expression and increased MMP2 activity, whereas the opposite effects were seen with an miR-17 inhibitor, suggesting that miR-17 may control the TIMP-MMP balance in these tissues. Luciferase reporter assays demonstrated that miR-17 regulated TIMP-1 and -2 expression.
  
  
  
  Our in vitro and in vivo studies taken together confirm that miR-17 directly regulates TIMP-1 and -2. Less dilated aortic BAV tissue may be in the initial stages of dilation under the control of miR-17-related miRNAs. New therapies that inhibit these miRNAs may prevent aortic dilation.
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin, China; Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Anatomy, Shanxi Medical University, Taiyuan, China.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Song
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Tsang
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Tumiati
authors.affiliation: Department of Pathology, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jagdish
authors.initials: J
authors.lastname: Butany
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Yau
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Maral
authors.initials: M
authors.lastname: Ouzounian
authors.affiliation: Laboratory of Medical Genetics, Harbin Medical University, Harbin, China.
authors.forename: Songbin
authors.initials: S
authors.lastname: Fu
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tirone E
authors.initials: TE
authors.lastname: David
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: renkeli@uhnresearch.ca.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D001018:Aortic Diseases / Q000209:etiology*; D001021:Aortic Valve / Q000002:abnormalities*; D000082882:Bicuspid Aortic Valve Disease; D004108:Dilatation, Pathologic / Q000209:etiology; D018450:Disease Progression; D005260:Female; D006349:Heart Valve Diseases / Q000150:complications*; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology
chemical_list: C524941:MIRN17 microRNA, human; D035683:MicroRNAs; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases
keywords: MMP; TIMP; aorta; bicuspid aortic valve