Abstract
Sirtuin3 (SIRT3), a class III histone deacetylase, is implicated in various cardiovascular diseases as a novel therapeutic target. SIRT3 has been proven to be cardioprotective in a model of Ang II-induced cardiac hypertrophy. However, a few small-molecule compounds targeting deacetylases could activate SIRT3. In this study, we generated a novel SIRT3 activator, 3-(2-bromo-4-hydroxyphenyl)-7-hydroxy-2H-chromen-2-one (SZC-6), through structural optimization of the first SIRT3 agonist C12. We demonstrated that SZC-6 directly bound to SIRT3 with Kd value of 15 μM, and increased SIRT3 deacetylation activity with EC50 value of 23.2 ± 3.3 µM. In neonatal rat cardiomyocytes (NRCMs), pretreatment with SZC-6 (10, 20, 40 µM) dose-dependently attenuated isoproterenol (ISO)-induced hypertrophic responses. Administration of SZC-6 (20, 40 and 60 mg·kg−1·d−1, s.c.) for 2 weeks starting from one week prior ISO treatment dose-dependently reversed ISO-induced impairment of diastolic and systolic cardiac function in wild-type mice, but not in SIRT3 knockdown mice. We showed that SZC-6 (10, 20, 40 µM) dose-dependently inhibited cardiac fibroblast proliferation and differentiation into myofibroblasts, which was abolished in SIRT3-knockdown mice. We further revealed that activation of SIRT3 by SZC-6 increased ATP production and rate of mitochondrial oxygen consumption, and reduced ROS, improving mitochondrial function in ISO-treated NRCMs. We also found that SZC-6 dose-dependently enhanced LKB1 phosphorylation, thereby promoting AMPK activation to inhibit Drp1-dependent mitochondrial fragmentation. Taken together, these results demonstrate that SZC-6 is a novel SIRT3 agonist with potential value in the treatment of cardiac hypertrophy partly through activation of the LKB1-AMPK pathway.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (U21A20419, 82173808, 82150204, 81872860, 82104157), Natural Science Foundation of Guangdong Province (2021B1515020100, 2022A1515012322, 2016A030311033), the Basic and Applied Basic Research Foundation of Guangdong Province (2020A1515410003), National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province, 2017B090903004), Guangzhou Basic and Applied Basic Research Project (202102020173) and Guangdong Provincial Key Laboratory of Construction Foundation (2017B030314030), the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (22qntd4510).
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PQL, YZ and XLZ were responsible for the experimental design and supervision of this project. ZYL performed most of the experiments and was the main writer of the manuscript. ZYL and PXW contributed to animal experiments. GQL contributed to the synthesis of compounds. JL contributed to the data analysis and manuscript writing. All authors made important suggestions regarding the manuscript.
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Li, Zy., Lu, Gq., Lu, J. et al. SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice. Acta Pharmacol Sin 44, 546–560 (2023). https://doi.org/10.1038/s41401-022-00966-8
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DOI: https://doi.org/10.1038/s41401-022-00966-8
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