Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation

Xiao-liang Dong1, Bao-hui Yuan2, Sheng-zhou Yu1, He Liu2, Xiao-hua Pan2, Jia Sun2, Li-long Pan1
1 Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China
2 School of Food Science and Technology, Jiangnan University, Wuxi 214122, China and 3State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China
Correspondence to: Jia Sun:, Li-long Pan:,
DOI: 10.1038/s41401-022-00963-x
Received: 20 March 2022
Accepted: 21 July 2022
Advance online: 2 September 2022


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.
Keywords: adriamycin; cardiotoxicity; cardiac fibrosis; cardiac fibroblasts; protein arginine methyltransferase 5; transforming growth factor-β1

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