Abstract
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 (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.
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Acknowledgements
This research work was 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) and “Double First-Class” University project (CPU2018GF06, CPU2018GF07).
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BYY and FL designed research; QL, FML, and WLR performed research; GYY, ZYF, and LZ contributed new reagents or analytic tools; FF and JPK analyzed data; FL and QL wrote the paper. All the authors have approved the manuscript.
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Lai, Q., Liu, Fm., Rao, Wl. et al. Aminoacylase-1 plays a key role in myocardial fibrosis and the therapeutic effects of 20(S)-ginsenoside Rg3 in mouse heart failure. Acta Pharmacol Sin 43, 2003–2015 (2022). https://doi.org/10.1038/s41401-021-00830-1
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DOI: https://doi.org/10.1038/s41401-021-00830-1
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