title: The microRNA-15 family inhibits the TGFβ-pathway in the heart.
abstract: OBJECTIVE
  The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGFβ-pathway is crucial for this remodelling. Here we tested the hypothesis that microRNAs in the overloaded heart regulate this remodelling process via inhibition of the TGFβ-pathway.
  
  
  RESULTS
  We show that the miRNA-15 family, which we found to be up-regulated in the overloaded heart in multiple species, inhibits the TGFβ-pathway by targeting of TGFBR1 and several other genes within this pathway directly or indirectly, including p38, SMAD3, SMAD7, and endoglin. Inhibition of miR-15b by subcutaneous injections of LNA-based antimiRs in C57BL/6 mice subjected to transverse aorta constriction aggravated fibrosis and to a lesser extent also hypertrophy.
  
  
  CONCLUSIONS
  We identified the miR-15 family as a novel regulator of cardiac hypertrophy and fibrosis acting by inhibition of the TGFβ-pathway.
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Anke J
authors.initials: AJ
authors.lastname: Tijsen
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Made
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Maarten M
authors.initials: MM
authors.lastname: van den Hoogenhof
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Wino J
authors.initials: WJ
authors.lastname: Wijnen
authors.affiliation: Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Elza D
authors.initials: ED
authors.lastname: van Deel
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Nina E
authors.initials: NE
authors.lastname: de Groot
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sergey
authors.initials: S
authors.lastname: Alekseev
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Fluiter
authors.affiliation: Department of Cardiology, Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.affiliation: Department of Molecular and Cell Biology, Centre of Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.affiliation: Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands e.e.creemers@amc.uva.nl.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D019556:COS Cells; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005355:Fibrosis; D056945:Hep G2 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055647:Rats, Transgenic; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; C570833:Mirn15 microRNA, mouse; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C534110:mirn15 microRNA, rat; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; C000625843:Tgfbr1 protein, rat
keywords: Fibrosis; Hypertrophy; TGFβ-pathway; miRNA-15 family