Published Online
on September 22, 2008

A more recent version of this article appeared on October 7, 2008

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Submitted on January 29, 2008
Accepted on July 15, 2008

Conditional Dicer Gene Deletion in the Postnatal Myocardium Provokes Spontaneous Cardiac Remodeling

Paula A. da Costa Martins PhD, Meriem Bourajjaj PhD, Monika Gladka MSc, Mara Kortland MSc, Ralph J. van Oort PhD, Yigal M. Pinto MD, PhD, Jeffery D. Molkentin PhD, and Leon J. De Windt PhD^*

From the Hubrecht Institute and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, Netherlands (P.A.d.C.M., M.B., M.G., M.K., R.J.v.O., L.J.D.W.); Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands (P.A.d.C.M., M.B., M.G., L.J.D.W.); Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands (Y.M.P.); and Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (J.D.M.).

^* To whom correspondence should be addressed. E-mail: l.j.dewindt{at}umcutrecht.nl.

Background—Dicer, an RNAse III endonuclease critical for processing of pre-microRNAs (miRNAs) into mature 22-nucleotide miRNAs, has proven a useful target to dissect the significance of miRNAs biogenesis in mammalian biology.

Methods and Results—To circumvent the embryonic lethality associated with germline null mutations for Dicer, we triggered conditional Dicer loss through the use of a tamoxifen-inducible Cre recombinase in the postnatal murine myocardium. Targeted Dicer deletion in 3-week-old mice provoked premature death within 1 week accompanied by mild ventricular remodeling and dramatic atrial enlargement. In the adult myocardium, loss of Dicer induced rapid and dramatic biventricular enlargement, accompanied by myocyte hypertrophy, myofiber disarray, ventricular fibrosis, and strong induction of fetal gene transcripts. Comparative miRNA profiling revealed a set of miRNAs that imply causality between miRNA depletion and spontaneous cardiac remodeling.

Conclusions—Overall, these results indicate that modifications in miRNA biogenesis affect both juvenile and adult myocardial morphology and function.

Key words: Dicer • genetics • heart failure • microRNA

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Clinical Summaries
Circulation 2008 118: 1519-1520. [Extract] [Full Text]

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