Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice

Yasufumi Katanasaka (), Harumi Yabe, Noriyuki Murata, Minori Sobukawa, Yuga Sugiyama, Hikaru Sato, Hiroki Honda, Yoichi Sunagawa, Masafumi Funamoto, Satoshi Shimizu, Kana Shimizu, Toshihide Hamabe-Horiike, Philip Hawke, Maki Komiyama, Kiyoshi Mori, Koji Hasegawa and Tatsuya Morimoto ()
Additional contact information
Yasufumi Katanasaka: University of Shizuoka
Harumi Yabe: University of Shizuoka
Noriyuki Murata: University of Shizuoka
Minori Sobukawa: University of Shizuoka
Yuga Sugiyama: University of Shizuoka
Hikaru Sato: University of Shizuoka
Hiroki Honda: University of Shizuoka
Yoichi Sunagawa: University of Shizuoka
Masafumi Funamoto: University of Shizuoka
Satoshi Shimizu: University of Shizuoka
Kana Shimizu: University of Shizuoka
Toshihide Hamabe-Horiike: University of Shizuoka
Philip Hawke: University of Shizuoka
Maki Komiyama: National Hospital Organization Kyoto Medical Center
Kiyoshi Mori: Shizuoka General Hospital
Koji Hasegawa: University of Shizuoka
Tatsuya Morimoto: University of Shizuoka

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46711-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46711-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46711-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().