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(7.5,15,30mg·kg-1·d-1,i.g.),or positive drug metoprolol(Met,5.14mg·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(25 μM)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 during the development of HF.Rg3 attenuates myocardial fibrosis to ameliorate HF through increasing ACY1 expression and inhibiting TGF-β1/Smad3 pathway,which provides some references for further development of anti-fibrotic drugs for HF.

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;Jiangsu Province Hospital of Chinese Medicine,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,China

[1]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-.Aminoacylase-1 plays a key role in myocardial fibrosis and the therapeutic effects of 20(S)-ginsenoside Rg3 in mouse heart failure)[J].中国药理学报（英文版）,2022(08):2003-2015

Aminoacylase,acetylglutamine,aminoacylase,ACY1,malonate,MTBM

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