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lüll Cardiovascular dysregulation of miR-17-92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis Danielson LS; Park DS; Rotllan N; Chamorro-Jorganes A; Guijarro MV; Fernandez-Hernando C; Fishman GI; Phoon CK; Hernando EFASEB J 2013[Apr]; 27 (4): 1460-7MicroRNA 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.|Animals[MESH]|Arrhythmias, Cardiac/*genetics/physiopathology[MESH]|Cardiomyopathy, Hypertrophic/*genetics/mortality/pathology/physiopathology[MESH]|Connexin 43/genetics/metabolism[MESH]|Disease Models, Animal[MESH]|Heart Defects, Congenital/genetics[MESH]|Mice[MESH]|Mice, Knockout[MESH]|MicroRNAs/*genetics[MESH]|PTEN Phosphohydrolase/genetics/metabolism[MESH] |