title: MicroRNA-133a protects against myocardial fibrosis and modulates electrical repolarization without affecting hypertrophy in pressure-overloaded adult hearts.
abstract: BACKGROUND
  MicroRNA (miR)-133a regulates cardiac and skeletal muscle differentiation and plays an important role in cardiac development. Because miR-133a levels decrease during reactive cardiac hypertrophy, some have considered that restoring miR-133a levels could suppress hypertrophic remodeling.
  
  
  OBJECTIVE
  To prevent the "normal" downregulation of miR-133a induced by an acute hypertrophic stimulus in the adult heart.
  
  
  RESULTS
  miR-133a is downregulated in transverse aortic constriction (TAC) and isoproterenol-induced hypertrophy, but not in 2 genetic hypertrophy models. Using MYH6 promoter-directed expression of a miR-133a genomic precursor, increased cardiomyocyte miR-133a had no effect on postnatal cardiac development assessed by measures of structure, function, and mRNA profile. However, increased miR-133a levels increased QT intervals in surface electrocardiographic recordings and action potential durations in isolated ventricular myocytes, with a decrease in the fast component of the transient outward K+ current, I(to,f), at baseline. Transgenic expression of miR-133a prevented TAC-associated miR-133a downregulation and improved myocardial fibrosis and diastolic function without affecting the extent of hypertrophy. I(to,f) downregulation normally observed post-TAC was prevented in miR-133a transgenic mice, although action potential duration and QT intervals did not reflect this benefit. miR-133a transgenic hearts had no significant alterations of basal or post-TAC mRNA expression profiles, although decreased mRNA and protein levels were observed for the I(to,f) auxiliary KChIP2 subunit, which is not a predicted target.
  
  
  CONCLUSIONS
  These results reveal striking differences between in vitro and in vivo phenotypes of miR expression, and further suggest that mRNA signatures do not reliably predict either direct miR targets or major miR effects.
authors.affiliation: Center for Pharmacogenomics, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Scot J
authors.initials: SJ
authors.lastname: Matkovich
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Tu
authors.forename: William H
authors.initials: WH
authors.lastname: Eschenbacher
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Dorn
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology; D003971:Diastole; D004562:Electrocardiography; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000235:genetics; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol / Q000009:adverse effects / Q000494:pharmacology; D051605:Kv Channel-Interacting Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D002316:Cardiotonic Agents; C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D018995:Myosin Heavy Chains; D007545:Isoproterenol