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

作　　者：Xiao-liang Dong Bao-hui Yuan Sheng-zhou Yu He Liu Xiao-hua Pan Jia Sun Li-long Pan 

机构地区：[1]Wuxi School of Medicine,Jiangnan University,Wuxi 214122,China [2]School of Food Science and Technology,Jiangnan University,Wuxi 214122,China [3]State Key Laboratory of Food Science and Technology,Jiangnan University,Wuxi 214122,China

出　　处：《Acta Pharmacologica Sinica》2023年第3期573-583,共11页中国药理学报（英文版）

基　　金：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);Wuxi Taihu Talent Project.

摘　　要：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 withα-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.

关 键 词：ADRIAMYCIN CARDIOTOXICITY cardiac fibrosis cardiac fibroblasts protein arginine methyltransferase 5 transforming growth factor-β1 

分 类 号：R285.5[医药卫生—中药学]