Cardiac myocyte miR-29 promotes pathological
remodeling of the heart by activating Wnt signaling
Yassine Sassi1,10, Petros Avramopoulos 1,2, Deepak Ramanujam1,2, Laurenz Grüter1, Stanislas Werfel1,
Simon Giosele1, Andreas-David Brunner1, Dena Esfandyari1,2, Aikaterini S. Papadopoulou3,4, Bart De Strooper3,4,
Norbert Hübner5,6,7, Regalla Kumarswamy8, Thomas Thum8, Xiaoke Yin9, Manuel Mayr 9,
Bernhard Laggerbauer1 & Stefan Engelhardt 1,2
Chronic cardiac stress induces pathologic hypertrophy and fibrosis of the myocardium. The
microRNA-29 (miR-29) family has been found to prevent excess collagen expression in
various organs, particularly through its function in fibroblasts. Here, we show that miR-29
promotes pathologic hypertrophy of cardiac myocytes and overall cardiac dysfunction. In a
mouse model of cardiac pressure overload, global genetic deletion of miR-29 or antimiR-29
infusion prevents cardiac hypertrophy and fibrosis and improves cardiac function. Targeted
deletion of miR-29 in cardiac myocytes in vivo also prevents cardiac hypertrophy and fibrosis,
indicating that the function of miR-29 in cardiac myocytes dominates over that in non-
myocyte cell types. Mechanistically, we found cardiac myocyte miR-29 to de-repress Wnt
signaling by directly targeting four pathway factors. Our data suggests that, cell- or tissue-
specific antimiR-29 delivery may have therapeutic value for pathological cardiac remodeling
and fibrosis.
DOI: 10.1038/s41467-017-01737-4 OPEN
1 Institute of Pharmacology and Toxicology, Technical University
Munich (TUM), 80802 Munich, Germany. 2 DZHK (German Center for
Cardiovascular
Research), partner site Munich Heart Alliance, 80802 Munich, Germany. 3
VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium. 4
Center for
Human Genetics and Leuven Institute for Neurodegenerative Disorders
(LIND), KU Leuven and Universitaire Ziekenhuizen, 3000 Leuven, Belgium.
5 Cardiovascular and Metabolic Sciences, Max-Delbrüeck-Center for
Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin,
Germany.
6DZHK (German Center for Cardiovascular Research), Partner Site Berlin,
10115 Berlin, Germany. 7 Charité-Universitätsmedizin, 10117 Berlin,
Germany.
8 Institute of Molecular and Translational Therapeutic Strategies
(IMTTS), Hannover Medical School, 30625 Hannover, Germany. 9 King’s
British Heart
Foundation Centre, King’s College London, SE5 9NU London, UK. 10Present
address: Mount Sinai, Cardiovascular Research Center, Icahn School of
Medicine
at Mount Sinai, New York, NY 10029, USA. Yassine Sassi and Petros
Avramopoulos contributed equally to this work. Correspondence and
requests for
materials should be addressed to S.E. (email: [email protected])
NATURE COMMUNICATIONS |8: 1614 |DOI: 10.1038/s41467-017-01737-4 |www.nature.com/naturecommunications 1
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0londonessays.com
M icroRNAs (miRNAs) are short, non-coding RNAm
olecules that
regulate gene expression at the post-transcriptional level1, and serious
estimates are that the
majority of genes and cellular processes are controlled by miR-
NAs or other non-coding RNA molecules2–4. miRNAs have
likewise been implicated in many diseases5, including those of the
cardiovascular system6. Of particular interest in this respect is
cardiac remodeling, a response of the myocardium to chronic
cardiac stress conditions, such as aortic stenosis, that is marked
by cardiac hypertrophy and fibrosis. Hypertrophy and fibrosis are
tightly interwoven, and mutually trigger each other7. Prominent
miRNAs with a documented role in cardiac myocyte hypertrophy
include miR-208, miR-133 and miR-212/1328–10, whereas a role
in fibrosis has been demonstrated for miR-21, miR-30, miR-133,
and miR-2911–15. In this regard, miR-29 has been reported to be
downregulated in several fibrosis-related diseases in rodents as
well as in humans, and has been shown to target mRNAs that
encode fibrosis-promoting proteins in different cell types/
organs16–21. In apparent agreement with this, experimental ele-
vation of miR-29 was found to repress collagen transcripts in
cultured cardiac fibroblasts13. Altogether, these findings sup-
ported the concept that enhancing miR-29 would be a promising
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