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

Laura S. Danielson, David S. Park, Noemi Rotllan, Aranzazu Chamorro-Jorganes, Maria V. Guijarro, Carlos Fernandez-Hernando, Glenn I. Fishman, Colin K.L. Phoon, Eva Hernando

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

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 dosedependent induction of dilated, hypertrophic cardiomyopathy, and arrhythmia inducibility in transgenic animals, which correlated with premature mortality (98.342.5 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.

Original languageEnglish
Pages (from-to)1460-1467
Number of pages8
JournalFASEB Journal
Volume27
Issue number4
DOIs
StatePublished - Apr 2013
Externally publishedYes

Keywords

  • Connexin43
  • MicroRNA
  • Mouse model
  • Pten

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