Key result
Fibroblast-specific PRMT5 deficiency or pharmacological inhibition with EPZ015666 significantly suppressed pressure overload-induced cardiac fibrosis and improved left ventricular dysfunction in mice.
Why the study?
The role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis was unknown.
Does PRMT5 inhibition or deletion prevent pressure overload-induced cardiac fibrosis and left ventricular dysfunction in preclinical models?
Does PRMT5 inhibition or deletion prevent pressure overload-induced cardiac fibrosis and left ventricular dysfunction in preclinical models?
PRMT5 regulates fibrotic gene transcription through histone methylation crosstalk, and its inhibition represents a potential therapeutic strategy for cardiac fibrosis and dysfunction.
Should not yet change HF practice; hypothesis-generating for PRMT5 inhibition in human cardiac fibrosis.
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.
No takes yet. Share an insight, caveat, or question.
Katanasaka et al. (2022) studied Pressure overload-induced cardiac fibrosis and left ventricular dysfunction. Fibroblast-specific PRMT5 deficiency and EPZ015666 vs. Wild-type mice / vehicle was evaluated on Cardiac fibrosis and fractional shortening. Fibroblast-specific PRMT5 deficiency or pharmacological inhibition with EPZ015666 significantly suppressed pressure overload-induced cardiac fibrosis and improved left ventricular dysfunction in mice.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: