title: MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis.
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.
  
  
  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.affiliation: From Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL.
authors.forename: Varun
authors.initials: V
authors.lastname: Nagpal
authors.affiliation: From Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL.
authors.forename: Rahul
authors.initials: R
authors.lastname: Rai
authors.affiliation: From Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Place
authors.affiliation: From Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL.
authors.forename: Sheila B
authors.initials: SB
authors.lastname: Murphy
authors.affiliation: From Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: From Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL.
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: From Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL. d-vaughan@northwestern.edu.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis*; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology
chemical_list: D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse
keywords: RNA sequence; angiotensin II; fibrosis; miR-125b; transforming growth factor