Aminoacylase-1 plays a key role in myocardial fibrosis and the therapeutic effects of 20(S)-ginsenoside Rg3 in mouse heart failure  

作　　者：Qiong Lai Fu-ming Liu Wang-lin Rao Guang-ying Yuan Zhao-yang Fan Lu Zhang Fei Fu Jun-ping Kou Bo-yang Yu Fang Li 

机构地区：[1]Jiangsu Key Laboratory of TCM Evaluation and Translational Research,Research Center for Traceability and Standardization of TCMs,School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing,211198,China [2]Jiangsu Province Hospital of Chinese Medicine,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing,210029,China

出　　处：《Acta Pharmacologica Sinica》2022年第8期2003-2015,共13页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81774150,81973506,82104437);Natural Science Foundation of Jiangsu Province(BK20210431);China Postdoctoral Science Foundation(2021M693519);National Innovation and Entrepreneurship Training Program for Undergraduate(202110316013Y);“Double First-Class”University project(CPU2018GF06,CPU2018GF07).

摘　　要：We previously found that the levels of metabolite N-acetylglutamine were significantly increased in urine samples of patients with heart failure(HF)and in coronary artery ligation(CAL)-induced HF mice,whereas the expression of its specific metabolic-degrading enzyme aminoacylase-1(ACY1)was markedly decreased.In the current study,we investigated the role of ACY1 in the pathogenesis of HF and the therapeutic effects of 20(S)-ginsenoside Rg3 in HF experimental models in vivo and in vitro.HF was induced in mice by CAL.The mice were administered Rg3(7.5,15,30 mg·kg^(-1)·d^(-1),i.g.),or positive drug metoprolol(Met,5.14 mg·kg^(-1)·d^(-1),i.g.),or ACY1 inhibitor mono-tert-butyl malonate(MTBM,5 mg·kg^(-1)·d^(-1),i.p.)for 14 days.We showed that administration of MTBM significantly exacerbated CAL-induced myocardial injury,aggravated cardiac dysfunction,and pathological damages,and promoted myocardial fibrosis in CAL mice.In Ang II-induced mouse cardiac fibroblasts(MCFs)model,overexpression of ACY1 suppressed the expression of COL3A1 and COL1A via inhibiting TGF-β1/Smad3 pathway,whereas ACY1-siRNA promoted the cardiac fibrosis responses.We showed that a high dose of Rg3(30 mg·kg^(-1)·d^(-1))significantly decreased the content of N-acetylglutamine,increased the expression of ACY1,and inhibited TGF-β1/Smad3 pathway in CAL mice;Rg3(25μM)exerted similar effects in Ang II-treated MCFs.Meanwhile,Rg3 treatment ameliorated cardiac function and pathological features,and it also attenuated myocardial fibrosis in vivo and in vitro.In Ang II-treated MCFs,the effects of Rg3 on collagen deposition and TGF-β1/Smad3 pathway were slightly enhanced by overexpression of ACY1,whereas ACY1 siRNA partially weakened the beneficial effects of Rg3,suggesting that Rg3 might suppress myocardial fibrosis through ACY1.Our study demonstrates that N-acetylglutamine may be a potential biomarker of HF and its specific metabolic-degrading enzyme ACY1 could be a potential therapeutic target for the prevention and treatment of myocardial fibrosis

关 键 词：heart failure myocardial fibrosis N-acetylglutamine aminoacylase-1 20(S)-ginsenoside Rg3 targeted metabolomics analysis 

分 类 号：R965[医药卫生—药理学]