Fibroblast-specific PRMT5 deficiency suppresses pressure overload-induced cardiac fibrosis and left ventricular dysfunction

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 reduced pressure overload-induced cardiac fibrosis and improved cardiac dysfunction. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppressed the expression of α-smooth muscle actin (α-SMA) induced by transforming growth factor-β (TGF-β) in cultured cardiac fibroblasts. TGF-β stimulation promoted the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increased PRMT5-mediated H3R2 symmetric dimethylation, and this increase was inhibited by knockdown of Smad3. TGF-β stimulation also increased H3K4 tri-methylation mediated by the WDR5/MLL1 lysine methylase complex, which recognizes H3R2 symmetric dimethylation. Finally, treatment with EPZ015666 significantly improved pressure overload-induced cardiac fibrosis and dysfunction. These findings reveal that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription through histone methylation crosstalk and plays a critical role in cardiac fibrosis and dysfunction.