Related Experiment Video
Updated: Jun 30, 2025
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice
Yasufumi Katanasaka1,2,3, Harumi Yabe4, Noriyuki Murata4
1Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. katana@u-shizuoka-ken.ac.jp.
Abstract:
Protein arginine methyltransferase 5 (PRMT5) is a well-known epigenetic regulatory enzyme. However, the role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis is unknown. Here we show that fibroblast-specific deletion of PRMT5 significantly reduces pressure overload-induced cardiac fibrosis and improves cardiac dysfunction in male mice. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppress α-smooth muscle actin (α-SMA) expression induced by transforming growth factor-β (TGF-β) in cultured cardiac fibroblasts. TGF-β stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-β stimulation increases H3K4 tri-methylation mediated by the WDR5/MLL1 methyltransferase complex, which recognizes H3R2 dimethylation. Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction.
Insights
Protein arginine methyltransferase 5 (PRMT5) regulates cardiac fibrosis by controlling gene transcription. Inhibiting PRMT5 reduces fibrosis and improves heart function, suggesting a therapeutic target for heart disease.
Area of Science:
- Epigenetics
- Cardiovascular Biology
- Molecular Mechanisms
Background:
- Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme.
- The role of PRMT5 in cardiac fibrosis is not well understood.
Purpose of the Study:
- To investigate the role of PRMT5 in cardiac fibrosis.
- To explore the mechanism of PRMT5-mediated gene transcription in cardiac fibroblasts.
Main Methods:
- Fibroblast-specific deletion of PRMT5 in mice.
- Inhibition of PRMT5 using EPZ015666.
- Transforming growth factor-β (TGF-β) stimulation of cardiac fibroblasts.
- Analysis of α-smooth muscle actin (α-SMA) expression.
- Chromatin immunoprecipitation to assess protein-DNA interactions and histone methylation.
- Smad3 and PRMT5 knockdown studies.
Main Results:
- Fibroblast-specific deletion of PRMT5 reduced cardiac fibrosis and improved cardiac dysfunction in mice.
- PRMT5 inhibition or knockdown suppressed TGF-β-induced α-SMA expression in cardiac fibroblasts.
- PRMT5/Smad3 complex recruitment to the α-SMA promoter was observed.
- PRMT5 inhibition reduced H3R2 symmetric dimethylation and subsequent H3K4 tri-methylation.
- EPZ015666 treatment improved pressure overload-induced cardiac fibrosis and dysfunction.
Conclusions:
- PRMT5 plays a critical role in cardiac fibrosis and dysfunction.
- PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription via histone methylation crosstalk.
- Targeting PRMT5 may be a potential therapeutic strategy for cardiac fibrosis.
