Anke J Tijsen1, Ingeborg van der Made1, Maarten M van den Hoogenhof1, Wino J Wijnen1, Elza D van Deel2, Nina E de Groot1, Sergey Alekseev1, Kees Fluiter3, Blanche Schroen4, Marie-José Goumans5, Jolanda van der Velden6, Dirk J Duncker2, Yigal M Pinto1, Esther E Creemers7. 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 e.e.creemers@amc.uva.nl.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.