title: Cardiovascular dysregulation of miR-17-92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis.
abstract: MicroRNA cluster miR-17-92 has been implicated in cardiovascular development and function, yet its precise mechanisms of action in these contexts are uncertain. This study aimed to investigate the role of miR-17-92 in morphogenesis and function of cardiac and smooth muscle tissues. To do so, a mouse model of conditional overexpression of miR-17-92 in cardiac and smooth muscle tissues was generated. Extensive cardiac functional studies identified a dose-dependent induction of dilated, hypertrophic cardiomyopathy, and arrhythmia inducibility in transgenic animals, which correlated with premature mortality (98.3 ± 42.5 d, P<0.0001). Expression analyses revealed the abundance of Pten transcript, a known miR-17-92 target, to be inversely correlated with miR-17-92 expression levels and heart size. In addition, we demonstrated through 3'-UTR luciferase assays and expression analyses that Connexin43 (Cx43) is a novel direct target of miR-19a/b and its expression is suppressed in transgenic hearts. Taken together, these data demonstrate that dysregulated expression of miR-17-92 during cardiovascular morphogenesis results in a lethal cardiomyopathy, possibly in part through direct repression of Pten and Cx43. This study highlights the importance of miR-17-92 in both normal and pathological functions of the heart, and provides a model that may serve as a useful platform to test novel antiarrhythmic therapeutics.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Danielson
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Chamorro-Jorganes
authors.forename: Maria V
authors.initials: MV
authors.lastname: Guijarro
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Hernando
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
authors.forename: Colin K L
authors.initials: CK
authors.lastname: Phoon
authors.forename: Eva
authors.initials: E
authors.lastname: Hernando
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006330:Heart Defects, Congenital / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism
chemical_list: D018031:Connexin 43; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse