Abstract
Long-term treatment with adriamycin (ADR) is associated with higher incidences of cumulative cardiotoxicity manifest as heart failure. ADR-induced cardiomyopathy is characterized by extensive fibrosis that is caused by cardiac fibroblast activation. To date, however, no specific treatment is available to alleviate ADR-induced cardiotoxicity. Protein arginine methyltransferase 5 (PRMT5), a major enzyme responsible for methylation of arginine, regulates numerous cellular processes such as cell differentiation. In the present study we investigated the role of PRMT5 in cardiac fibrosis. Mice were administered ADR (3 mg/kg, i.p., every 2 days) for 2 weeks. We showed that aberrant PRMT5 expression was largely co-localized with α-SMA-positive activated cardiac fibroblasts in ADR-injected mice and in ADR-treated cardiac fibroblasts in vitro. PRMT5-overexpression exacerbated, whereas PRMT5 knockdown alleviated ADR-induced cardiac fibrosis in vivo and TGF-β1-induced cardiac fibroblast activation in vitro. We demonstrated that PRMT5-overexpression enhanced methylated-Smad3 levels in vivo and in vitro. Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-β1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity.
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Acknowledgements
This work was financially supported by grants from the National Natural Science Foundation of China (Grant nos: 81973322, 81902706), Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province, the Fundamental Research Funds for the Central Universities (Grant nos: JUSRP221037, JUSRP22007, JUSRP122055), Jiangsu Province “Six Summit Talents” Program (Grant no: YY‐038) and Wuxi Taihu Talent Project.
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LLP and JS designed the study and revised the paper. XLD, SZY, BHY, and HL performed experiments. XLD and XHP analysed the data. XLD wrote the paper. LLP and JS reviewed the paper.
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Dong, Xl., Yuan, Bh., Yu, Sz. et al. Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation. Acta Pharmacol Sin 44, 573–583 (2023). https://doi.org/10.1038/s41401-022-00963-x
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DOI: https://doi.org/10.1038/s41401-022-00963-x
