Journal
FASEB JOURNAL
Volume 27, Issue 4, Pages 1460-1467Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.12-221994
Keywords
microRNA; mouse model; connexin43; Pten
Categories
Funding
- New York University (NYU) Cancer Institute Cancer Center [5P30CA016087-32]
- NYU-Health and Hospitals Corp.
- Clinical and Translational Science Institute
- National Center for Advancing Translational Sciences/U.S. National Institutes of Health (NIH) [UL1 TR000038]
- NIH/National Center for Research Resources [1ULIRR029893]
- Liddy Shriver Sarcoma Initiative
- LMS Direct Research Foundation
- Edna's Foundation of Hope
- NIH [R01HL82727, S10RR026881, R01HL106063, R01HL107953]
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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.-Danielson, L. S., Park, D. S., Rotllan, N., Chamorro-Jorganes, A., Guijarro, M. V., Fernandez-Hernando, C., Fishman, G. I., Phoon, C. K. L., Hernando, E. Cardiovascular dysregulation of miR-17-92 causes a lethal hypertrophic cardiomyopathy and arrhythmogenesis. FASEB J. 27, 1460-1467 (2013). www.fasebj.org
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