| First Author | Katanasaka Y | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 2472 |
| PubMed ID | 38503742 | Mgi Jnum | J:347432 |
| Mgi Id | MGI:7615582 | Doi | 10.1038/s41467-024-46711-z |
| Citation | Katanasaka Y, et al. (2024) Fibroblast-specific PRMT5 deficiency suppresses cardiac fibrosis and left ventricular dysfunction in male mice. Nat Commun 15(1):2472 |
| abstractText | 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 alpha-smooth muscle actin (alpha-SMA) expression induced by transforming growth factor-beta (TGF-beta) in cultured cardiac fibroblasts. TGF-beta stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of alpha-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-beta 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-beta/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction. |
