title: Inhibition of miR-208b improves cardiac function in titin-based dilated cardiomyopathy.
abstract: BACKGROUND
  Dilated cardiomyopathy (DCM) is the result of maladaptive cardiac remodeling, which involves microRNA regulation. In turn, microRNAs can contribute to the remodeling process by post-transcriptional modulation of gene expression networks. The exact role of microRNAs in the pathogenesis of DCM is largely unknown. Here, we used an inducible DCM mouse model that carries a human truncation mutation in the sarcomeric protein titin to dissect microRNA pathways in DCM development.
  
  
  RESULTS
  MicroRNA microarray studies revealed up-regulation of microRNA-208b in the myocardium of DCM mice and DCM patients (p<0.05 compared to controls). In order to investigate the effect of microRNA-208b on cardiac remodeling, loss-of-function and gain-of-function studies were performed by repetitive injections of LNA-modified microRNA-208b mimics and antimiR-208b. MiR-208b overexpression resulted in cardiac hypertrophy, whereas miR-208b antagonisation prevented transition of adaptive to maladaptive remodeling in the DCM mouse model. In vitro studies identified several pro-hypertrophic transcription factors as potential targets of miR-208b, suggesting that microRNA-208b plays an important role in cardiac development and growth. MiR-208b was also upregulated in DCM patients, but not in heart failure patients due to ischemic heart disease or myocarditis.
  
  
  CONCLUSIONS
  Our data suggests that miR-208b is involved in the remodeling process and pathogenesis of DCM by post-transcriptional gene expression modulation. MicroRNA-208b might be a novel therapeutic target for DCM.
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schötterl
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Backes
authors.affiliation: Abteilung für Molekulare Pathologie, Eberhard Karls Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Brunner
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: Julia Kelley
authors.initials: JK
authors.lastname: Hahn
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Ionesi
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: Parwez
authors.initials: P
authors.lastname: Aidery
authors.affiliation: Zentrum für medizinische Forschung (ZMF), Universitätsmedizin Mannheim, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Institute for Integrative Pathophysiology, Universitätsmedizin Mannheim, Mannheim, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.affiliation: Abteilung für Molekulare Pathologie, Eberhard Karls Universitätsklinikum Tübingen, Tübingen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Department of Cardiology and Cardiovascular Diseases, Eberhard Karls University, Tübingen, Germany. Electronic address: michael.gramlich@med.uni-tuebingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Gramlich
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D064211:Connectin / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D064211:Connectin; D035683:MicroRNAs; C543978:Mirn208 microRNA, mouse; D012313:RNA
keywords: Animal models of human disease; Cardiomyopathy; Genetics; Heart failure; MicroRNA; Titin