The microRNA-15 family inhibits the TGF beta-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-Jose 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 TGF beta-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-Jose Goumans, Jolanda van der Velden, Dirk J. Duncker, Yigal M. Pinto, Esther E. Creemers^*

^*Corresponding author for this work

Cardiologie

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Aims The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGF beta-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 TGFb-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 TGFb-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 TGF beta-pathway.

Original language	English
Pages (from-to)	61-71
Journal	Cardiovascular Research
Volume	104
Issue number	1
DOIs	https://doi.org/10.1093/cvr/cvu184
Publication status	Published - 1 Oct 2014

Keywords

Fibrosis
Hypertrophy
miRNA-15 family
TGF beta-pathway

Access to Document

10.1093/cvr/cvu184

Cite this

Tijsen, A. J., van der Made, I., van den Hoogenhof, M. M., Wijnen, W. J., van Deel, E. D., de Groot, N. E., Alekseev, S., Fluiter, K., Schroen, B., Goumans, M.-J., van der Velden, J., Duncker, D. J., Pinto, Y. M., & Creemers, E. E. (2014). The microRNA-15 family inhibits the TGF beta-pathway in the heart. Cardiovascular Research, 104(1), 61-71. https://doi.org/10.1093/cvr/cvu184

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title = "The microRNA-15 family inhibits the TGF beta-pathway in the heart",

abstract = "Aims The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGF beta-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 TGFb-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 TGFb-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 TGF beta-pathway.",

keywords = "Fibrosis, Hypertrophy, miRNA-15 family, TGF beta-pathway",

author = "Tijsen, {Anke J.} and {van der Made}, Ingeborg and {van den Hoogenhof}, {Maarten M.} and Wijnen, {Wino J.} and {van Deel}, {Elza D.} and {de Groot}, {Nina E.} and Sergey Alekseev and Kees Fluiter and Blanche Schroen and Marie-Jose Goumans and {van der Velden}, Jolanda and Duncker, {Dirk J.} and Pinto, {Yigal M.} and Creemers, {Esther E.}",

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doi = "10.1093/cvr/cvu184",

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AU - Tijsen, Anke J.

AU - van der Made, Ingeborg

AU - van den Hoogenhof, Maarten M.

AU - Wijnen, Wino J.

AU - van Deel, Elza D.

AU - de Groot, Nina E.

AU - Alekseev, Sergey

AU - Fluiter, Kees

AU - Schroen, Blanche

AU - Goumans, Marie-Jose

AU - van der Velden, Jolanda

AU - Duncker, Dirk J.

AU - Pinto, Yigal M.

AU - Creemers, Esther E.

PY - 2014/10/1

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N2 - Aims The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGF beta-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 TGFb-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 TGFb-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 TGF beta-pathway.

AB - Aims The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGF beta-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 TGFb-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 TGFb-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 TGF beta-pathway.

KW - Fibrosis

KW - Hypertrophy

KW - miRNA-15 family

KW - TGF beta-pathway

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