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

• Published in: Cardiovascular research Vol. 104; no. 1; pp. 61 - 71
• Main Authors: Tijsen, Anke J, van der Made, Ingeborg, van den Hoogenhof, Maarten M, Wijnen, Wino J, van Deel, Elza D, de Groot, Nina E, Alekseev, Sergey, Fluiter, Kees, Schroen, Blanche, Goumans, Marie-José, van der Velden, Jolanda, Duncker, Dirk J, Pinto, Yigal M, Creemers, Esther E
• Format: Journal Article
• Language: English
• Published: England 01.10.2014
• Subjects: 3' Untranslated Regions; Animals; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - physiopathology; Cardiomyopathies - genetics; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cardiomyopathies - physiopathology; Case-Control Studies; Cercopithecus aethiops; COS Cells; Disease Models, Animal; Fibrosis; Hep G2 Cells; Humans; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Myocytes, Cardiac - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Rats, Transgenic; 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; miRNA-15 family; TGFβ-pathway; Fibrosis; Hypertrophy
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvu184

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