Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 42, Pages 16850-16855Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1316764110
Keywords
fibrosis; dermal injury; MAP kinase signaling; granulation tissue
Categories
Funding
- American Heart Association
- joint University of Rochester/Moulder Center for Drug Discovery Pilot Award
- Aab Cardiovascular Research Institute at the University of Rochester School of Medicine and Dentistry
- National Institutes of Health (NIH) [HL-110869]
- Moss Heart Fund
- NIH [GM-031321, U01-HL-100401, HL-077439, HL-111665, HL-093039]
- AHA-Jon Holden DeHaan Foundation
- Cancer Prevention and Research Institute of Texas
- American Heart Association-Jon Holden DeHaan Foundation [0970518N]
- Foundation Leducq Networks of Excellence
- Robert A. Welch Foundation [1-0025]
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Myocardin-related transcription factors (MRTFs) regulate cellular contractility and motility by associating with serum response factor (SRF) and activating genes involved in cytoskeletal dynamics. We reported previously that MRTF-A contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction. Here, we show that forced expression of MRTF-A in dermal fibroblasts stimulates contraction of a collagen matrix, whereas contractility of MRTF-A null fibroblasts is impaired under basal conditions and in response to TGF-beta 1 stimulation. We also identify an isoxazole ring-containing small molecule, previously shown to induce smooth muscle alpha-actin gene expression in cardiac progenitor cells, as an agonist of myofibroblast differentiation. Isoxazole stimulates myofibroblast differentiation via induction of MRTF-A-dependent gene expression. The MRTF-SRF signaling axis is activated in response to skin injury, and treatment of dermal wounds with isoxazole accelerates wound closure and suppresses the inflammatory response. These results reveal an important role for MRTF-SRF signaling in dermal myofibroblast differentiation and wound healing and suggest that targeting MRTFs pharmacologically may prove useful in treating diseases associated with inappropriate myofibroblast activity.
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