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.

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