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Cited by 27Liver physiology and pathologyTGF-β signaling in diseasesLiver Disease Diagnosis and Treatment

Myocardin and myocardin-related transcription factor-A synergistically mediate actin cytoskeletal-dependent inhibition of liver fibrogenesis

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Shi, Zengdun, Ren, Mudan, Rockey, Don C.·2020·American Journal of Physiology-Gastrointestinal and Liver Physiology
DOI 10.1152/ajpgi.00302.2019PMC PMC7099496
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Abstract

Activation of hepatic stellate cells (HSCs), characterized by development of a robust actin cytoskeleton and expression of abundant extracellular matrix (ECM) proteins, such as type 1 collagen (COL.1), is a central cellular and molecular event in liver fibrosis. It has been demonstrated that HSCs express both myocardin and myocardin-related transcription factor-A (MRTF-A). However, the biological effects of myocardin and MRTF-A on HSC activation and liver fibrosis, as well as the molecular mechanism under the process, remain unclear. Here, we report that myocardin and MRTF-A’s expression and nuclear accumulation are prominently increased during the HSC activation process, accompanied by robust activation of actin cytoskeleton dynamics. Targeting myocardin and MRTF-A binding and function with a novel small molecule, CCG-203971, led to dose-dependent inhibition of HSC actin cytoskeleton dynamics and abrogated multiple functional features of HSC activation (i.e., HSC contraction, migration and proliferation) and decreased COL.1 expression in vitro and liver fibrosis in vivo. Mechanistically, blocking the myocardin and MRTF-A nuclear translocation pathway with CCG-203971 directly inhibited myocardin/MRTF-A-mediated serum response factor (SRF), and Smad2/3 activation in the COL.1α2 promoter and indirectly abrogated actin cytoskeleton-dependent regulation of Smad2/3 and Erk1/2 phosphorylation and their nuclear accumulation. Finally, there was no effect of CCG-203971 on markers of inflammation, suggesting a direct effect of the compound on HSCs and liver fibrosis. These data reveal that myocardin and MRTF-A are two important cotranscriptional factors in HSCs and represent entirely novel therapeutic pathways that might be targeted to treat liver fibrosis. NEW & NOTEWORTHY Myocardin and myocardin-related transcription factor-A (MRTF-A) are upregulated in activated hepatic stellate cells (HSCs) in vitro and in vivo, closely associated with robustly increased actin cytoskeleton remodeling. Targeting myocardin and MRTF-A by CCG-203971 leads to actin cytoskeleton-dependent inhibition of HSC activation, reduced cell contractility, impeded cell migration and proliferation, and decreased COL.1 expression in vitro and in vivo. Dual expression of myocardin and MRTF-A in HSCs may represent novel therapeutic targets in liver fibrosis.

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  • Pharmaceutical inhibition of MRTFA and YAP cofactors significantly attenuates extracellular matrix deposition and expression of profibrotic regulators.

    “Pharmaceutical inhibition of these cofactors significantly attenuates ECM deposition and the expression of profibrotic regulators [18, 19].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [19]

    The Results (page unavailable) report that CCG-203971, targeting myocardin and MRTF-A, reduced liver fibrosis, collagen expression, and the profibrotic regulators TGF-β and ET-1 in mice. The paper does not report inhibition of YAP, so it supports the MRTF-A portion of the attribution but not the YAP portion. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Genes related to ECM deposition and actin contractility such as Flna and Itgb1 showed differential expression.

    “In addition, genes related to ECM deposition and actin contractility such as Flna and Itgb1 showed differential expression as well [17, 19, 61].”

    From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [19]

    The Results (page unavailable) report altered expression of COL.1, an ECM component, and changes in hepatic stellate-cell contractility. The paper does not report differential expression of the named genes Flna or Itgb1, so it supports the broader biological context but not those examples. (LLM, conf=0.78)

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Cited by

Sorted by citations

Authors
Shi, Z., Ren, M., & Rockey, D. C.
Affiliations
Medical University of South Carolina (US)
Corresponding author
Rockey, Don C.
ORCID
Venue
American Journal of Physiology-Gastrointestinal and Liver Physiology
Publisher
American Physiological Society
Published
2020-03-01
Volume
318
Issue
3
Pages
G504-G517
ISSN
  • 0193-1857 (ISSN-L)
  • 1522-1547
DOI
10.1152/ajpgi.00302.2019
PMC
PMC7099496
OpenAlex
W3000385169
Cited by
27
References
3
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 3 · 2020: 1
FWCI
2.35
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Figshare (cc-by)
Funders
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK 098819)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
myocardin, MRTF-A, liver fibrosis, hepatic stellate cells, actin cytoskeleton, serum response factor, Smad2/3, ERK1/2, type I collagen, extracellular matrix, hepatic stellate cell activation, cell proliferation and migration, antifibrotic therapy
MeSH terms
Collagen Type I, alpha 1 Chain, Myocardin, Animals, Cell Movement, Cells, Cultured, Extracellular Matrix, Liver, Liver Cirrhosis, Experimental, Male, Mice, Inbred BALB C, Actin Cytoskeleton, Nipecotic Acids, Nuclear Proteins, Phosphorylation, Time Factors, Transcription Factors, Signal Transduction, Trans-Activators, Up-Regulation, Rats, Sprague-Dawley, Collagen Type I, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Smad Proteins, Receptor-Regulated, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury

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