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

Academic Article

Abstract

  • 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.
  • Authors

    Published In

  • Circulation  Journal
  • Keywords

  • RNA sequence, angiotensin II, fibrosis, miR-125b, transforming growth factor, Animals, Cell Proliferation, Cells, Cultured, Fibroblasts, Fibrosis, Gene Knockdown Techniques, Heart Diseases, Humans, Mice, Mice, Inbred C57BL, MicroRNAs, Myofibroblasts
  • Digital Object Identifier (doi)

    Author List

  • Nagpal V; Rai R; Place AT; Murphy SB; Verma SK; Ghosh AK; Vaughan DE
  • Start Page

  • 291
  • End Page

  • 301
  • Volume

  • 133
  • Issue

  • 3