Cardiovascular dysregulation of miR-17-92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis

• Published in: The FASEB journal Vol. 27; no. 4; p. 1460
• Main Authors: Danielson, Laura S, Park, David S, Rotllan, Noemi, Chamorro-Jorganes, Aranzazu, Guijarro, Maria V, Fernandez-Hernando, Carlos, Fishman, Glenn I, Phoon, Colin K L, Hernando, Eva
• Format: Journal Article
• Language: English
• Published: United States 01.04.2013
• Subjects: Animals; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - physiopathology; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - mortality; Cardiomyopathy, Hypertrophic - pathology; Cardiomyopathy, Hypertrophic - physiopathology; Connexin 43 - genetics; Connexin 43 - metabolism; Disease Models, Animal; Heart Defects, Congenital - genetics; Mice; Mice, Knockout; MicroRNAs - genetics; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism
• ISSN: 1530-6860
• DOI: 10.1096/fj.12-221994

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.