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

Varun Nagpal, Rahul Rai, Aaron T. Place, Sheila B. Murphy, Suresh K. Verma, Asish K. Ghosh, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)291-301
Number of pages11
JournalCirculation
Volume133
Issue number3
DOIs
StatePublished - Jan 19 2016

Keywords

  • Angiotensin II
  • RNA sequence
  • fibrosis
  • miR-125b
  • transforming growth factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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