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Updated: Sep 16, 2025
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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
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Yoda1 Inhibits TGFβ-Induced Cardiac Fibroblast Activation via a BRD4-Dependent Pathway
Perwez Alam1,2, Sara M Stiens1, Hunter J Bowles1
1Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
Cells
|July 11, 2025
Summary
This study reveals that Yoda1 inhibits cardiac fibroblast activation by targeting BRD4, not Piezo1, offering new therapeutic strategies for heart fibrosis. This research explores ion channel roles in fibrosis.
Area of Science:
- Cardiovascular Biology
- Cellular Physiology
- Pharmacology
Background:
- Fibrosis, excessive extracellular matrix deposition, impairs tissue function and is central to heart failure progression.
- Cardiac fibroblasts (CFs) activate into myofibroblasts, driving pathological matrix accumulation, a process regulated by transforming growth factor-beta (TGFβ).
- The role of ion channels, particularly calcium-activated potassium (KCa) channels, in fibroblast activation is an emerging area of research.
Purpose of the Study:
- To investigate the role of ion channels in TGFβ-induced cardiac fibroblast activation.
- To elucidate the mechanism by which Yoda1, a Piezo1 agonist, modulates this activation process.
- To identify molecular mediators involved in Yoda1's effects on fibroblast activation.
Main Methods:
- Utilized NIH/3T3 fibroblasts to study TGFβ-induced activation.
- Examined the effects of tetraethylammonium (TEA)-sensitive potassium channels and specific subtypes (BK, SK, IK).
- Investigated Yoda1's mechanism via transcriptomic analysis and identified Bromodomain-containing protein 4 (BRD4) as a key mediator, using inhibitors (JQ1, ZL0454) and overexpression studies.
Main Results:
- TGFβ-induced fibroblast activation was regulated by TEA-sensitive potassium channels, independent of specific K⁺ channel subtypes.
- Yoda1 inhibited TGFβ-induced fibroblast activation through a Piezo1-independent pathway.
- Yoda1 modulated fibrotic gene expression pathways, with BRD4 identified as a critical mediator; BRD4 inhibition suppressed Periostin (Postn) expression, while BRD4 overexpression attenuated Yoda1's inhibitory effects.
Conclusions:
- Yoda1 exerts anti-fibrotic effects on cardiac fibroblasts via a Piezo1-independent mechanism involving BRD4.
- BRD4 is a crucial mediator in the regulation of TGFβ-induced fibroblast activation and ECM production.
- These findings offer novel insights into targeting ion channels and BRD4 for potential therapeutic interventions against cardiac fibrosis.
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