MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis

Circulation. 2016 Jan 19;133(3):291-301. doi: 10.1161/CIRCULATIONAHA.115.018174. Epub 2015 Nov 19.


Background: Cardiac fibrosis is the pathological consequence of stress-induced fibroblast proliferation and fibroblast-to-myofibroblast transition. MicroRNAs have been shown to play a central role in the pathogenesis of cardiac fibrosis. We identified a novel miRNA-driven mechanism that promotes cardiac fibrosis via regulation of multiple fibrogenic pathways.

Methods and results: Using a combination of in vitro and in vivo studies, we identified that miR-125b is a novel regulator of cardiac fibrosis, proliferation, and activation of cardiac fibroblasts. We demonstrate that miR-125b is induced in both fibrotic human heart and murine models of cardiac fibrosis. In addition, our results indicate that miR-125b is necessary and sufficient for the induction of fibroblast-to-myofibroblast transition by functionally targeting apelin, a critical repressor of fibrogenesis. Furthermore, we observed that miR-125b inhibits p53 to induce fibroblast proliferation. Most importantly, in vivo silencing of miR-125b by systemic delivery of locked nucleic acid rescued angiotensin II-induced perivascular and interstitial fibrosis. Finally, the RNA-sequencing analysis established that miR-125b altered the gene expression profiles of the key fibrosis-related genes and is a core component of fibrogenesis in the heart.

Conclusions: In conclusion, miR-125b is critical for induction of cardiac fibrosis and acts as a potent repressor of multiple anti-fibrotic mechanisms. Inhibition of miR-125b may represent a novel therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.

Keywords: RNA sequence; angiotensin II; fibrosis; miR-125b; transforming growth factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Gene Knockdown Techniques
  • Heart Diseases / metabolism*
  • Heart Diseases / pathology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / biosynthesis*
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology


  • MicroRNAs
  • Mirn125 microRNA, mouse