The microRNA-15 family inhibits the TGFβ-pathway in the heart

Anke J Tijsen; Ingeborg van der Made; Maarten M van den Hoogenhof; Wino J Wijnen; Elza D van Deel; Nina E de Groot; Sergey Alekseev; Kees Fluiter; Blanche Schroen; Marie-José Goumans; Jolanda van der Velden; Dirk J Duncker; Yigal M Pinto; Esther E Creemers

doi:10.1093/cvr/cvu184

The microRNA-15 family inhibits the TGFβ-pathway in the heart

Cardiovasc Res. 2014 Oct 1;104(1):61-71. doi: 10.1093/cvr/cvu184. Epub 2014 Aug 7.

Affiliations

¹ Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
² Department of Cardiology, Thoraxcenter, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.
³ Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
⁴ Department of Cardiology, Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
⁵ Department of Molecular and Cell Biology, Centre of Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
⁶ Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
⁷ Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands [email protected].

PMID: 25103110
DOI: 10.1093/cvr/cvu184

Abstract

Aims: The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGFβ-pathway is crucial for this remodelling. Here we tested the hypothesis that microRNAs in the overloaded heart regulate this remodelling process via inhibition of the TGFβ-pathway.

Methods and results: We show that the miRNA-15 family, which we found to be up-regulated in the overloaded heart in multiple species, inhibits the TGFβ-pathway by targeting of TGFBR1 and several other genes within this pathway directly or indirectly, including p38, SMAD3, SMAD7, and endoglin. Inhibition of miR-15b by subcutaneous injections of LNA-based antimiRs in C57BL/6 mice subjected to transverse aorta constriction aggravated fibrosis and to a lesser extent also hypertrophy.

Conclusion: We identified the miR-15 family as a novel regulator of cardiac hypertrophy and fibrosis acting by inhibition of the TGFβ-pathway.

Keywords: Fibrosis; Hypertrophy; TGFβ-pathway; miRNA-15 family.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
COS Cells
Cardiomegaly / genetics
Cardiomegaly / metabolism*
Cardiomegaly / pathology
Cardiomegaly / physiopathology
Cardiomyopathies / genetics
Cardiomyopathies / metabolism*
Cardiomyopathies / pathology
Cardiomyopathies / physiopathology
Case-Control Studies
Chlorocebus aethiops
Disease Models, Animal
Fibrosis
Hep G2 Cells
Humans
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism*
Myocytes, Cardiac / metabolism*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Rats, Transgenic
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / genetics
Receptors, Transforming Growth Factor beta / metabolism
Signal Transduction*
Smad3 Protein / genetics
Smad3 Protein / metabolism
Smad7 Protein / genetics
Smad7 Protein / metabolism
Transfection
Transforming Growth Factor beta / metabolism*
Up-Regulation
Ventricular Remodeling*
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

3' Untranslated Regions
MIRN15 microRNA, human
MicroRNAs
Mirn15 microRNA, mouse
Receptors, Transforming Growth Factor beta
Smad3 Protein
Smad7 Protein
Transforming Growth Factor beta
mirn15 microRNA, rat
Protein Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
Receptor, Transforming Growth Factor-beta Type I
TGFBR1 protein, human
Tgfbr1 protein, mouse
Tgfbr1 protein, rat