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

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.

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc)

“…Notably, fibroblast-specific deletion of PRMT5 significantly reduced pressure overload-induced cardiac fibrosis. PRMT5 has been shown to regulate transforming growth factor beta (TGF-β)/Smad3-dependent fibrotic gene transcription, potentially through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction 45. Similarly, the contribution of PRMT5 to fibrosis has been confirmed in an Adriamycin-induced cardiac fibrosis model 46.…”

“…PRMT5 has been reported to regulate T cells through various pathways, including promoting retinoid-related orphan receptor (ROR)-γt activity and adjusting the Klf2-S1pr1 pathway 41 42. Arginine methylation mediated by PRMTs has emerged as a critical mechanism implicated in fibrosis 43–47. Notably, fibroblast-specific deletion of PRMT5 significantly reduced pressure overload-induced cardiac fibrosis.…”