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.

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Cardiovascular Research
Department of Cardiology

Tijsen, A. J., Van Der Made, I., van den Hoogenhof, M., Wijnen, W. J., van Deel, E., De Groot, N. E., … Creemers, E. E. (2014). The microRNA-15 family inhibits the TGFβ-pathway in the heart. Cardiovascular Research, 104(1), 61–71. doi:10.1093/cvr/cvu184