Preventing hypocontractility-induced fibroblast expansion alleviates dilated cardiomyopathy

  • Science. 2025 Sep 11:eadv9157. doi: 10.1126/science.adv9157.
Ross C Bretherton  1  2  3 ,  Isabella M Reichardt  1  2  3 ,  Kristin A Zabrecky  2  3  4 ,  Abigail Nagle  1  2  3 ,  Logan R J Bailey  2  3  5 ,  Darrian Bugg  2  3  5 ,  Sasha Smolgovsky  2  3  5 ,  Amy L Gifford  2  3  5 ,  Timothy S McMillen  1  6 ,  Alex J Goldstein  2  5 ,  Kristina B Kooiker  2  3  7 ,  Galina V Flint  1 ,  Amy Martinson  2  3  5 ,  Jagdambika Gunaje  2  3  5 ,  Franziska Koser  8 ,  Elizabeth Plaster  2  3  5 ,  Wolfgang A Linke  8 ,  Michael Regnier  1  2  3  9 ,  Farid Moussavi-Harami  2  3  5  7  9 ,  Nathan J Sniadecki  1  2  3  5  9  10 ,  Cole A DeForest  1  2  11  12  13  14 ,  Jennifer Davis  1  2  3  5  9
Affiliations
  • 1. Department of Bioengineering, University of Washington, Seattle, WA, USA.
  • 2. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
  • 3. Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA.
  • 4. Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
  • 5. Department of Lab Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • 6. Department of Anesthesiology, University of Washington, Seattle, WA, USA.
  • 7. Division of Cardiology, University of Washington, Seattle, WA, USA.
  • 8. Institute of Physiology II, University of Münster, Münster, Germany.
  • 9. Center for Translational Muscle Research, University of Washington, Seattle, WA, USA.
  • 10. Department of Mechanical Engineering, University of Washington, Seattle, WA, USA.
  • 11. Department of Chemical Engineering, University of Washington, Seattle, WA, USA.
  • 12. Department of Chemistry, University of Washington, Seattle, WA, USA.
  • 13. Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA, USA.
  • 14. Institute for Protein Design, University of Washington, Seattle, WA, USA.
PMID: 40934290 DOI: 10.1126/science.adv9157
Abstract

Cardiomyocyte hypocontractility underlies inherited dilated cardiomyopathy (DCM). Yet, whether fibroblasts modify DCM phenotypes remains unclear despite their regulation of fibrosis, which strongly predicts disease severity. Expression of a hypocontractility-linked sarcomeric variant in mice triggered cardiac fibroblast expansion from the de novo formation of hyperproliferative-mechanosensitized fibroblast states, which occurred prior to eccentric myocyte remodeling. Initially this fibroblast response reorganized fibrillar Collagen and stiffened the myocardium albeit without depositing fibrotic tissue. These adaptations coincided with heightened matrix-integrin receptor interactions and diastolic tension sensation at focal adhesions within fibroblasts. Targeted p38 deletion arrested these cardiac fibroblast responses in DCM mice, which prevented cardiomyocyte remodeling and improved contractility. In conclusion, p38-mediated fibroblast responses were essential regulators of DCM severity, marking a potential cellular target for therapeutic intervention.

Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-15768
    Ilomastat
    99.14%, MMP Inhibitor
    target: MMP
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