SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice

• Published in: Acta pharmacologica Sinica 2023-03, Vol.44 (3), p.546-560
• Main Authors: Li, Ze-yu, Lu, Guo-qing, Lu, Jing, Wang, Pan-xia, Zhang, Xiao-lei, Zou, Yong, Liu, Pei-qing
• Format: Article
• Language: English
• Subjects: Adenosine; Agonists; Alzheimer's disease; AMP-Activated Protein Kinases - metabolism; Angiotensin II; Animals; Biomedical and Life Sciences; Biomedicine; Cardiomegaly - chemically induced; Cardiomyocytes; Cardiovascular disease; Cardiovascular diseases; Chemotherapy; Chinese medicine; Deacetylation; Diabetes; Drug dosages; Heart; Histone deacetylase; Hypertrophy; Immunology; Internal Medicine; Isoproterenol; Laboratories; LKB1 protein; Medical Microbiology; Medical research; Metabolism; Mice; Mitochondria; Myocytes, Cardiac - metabolism; Neonates; Oxidative stress; Oxygen consumption; Pharmaceutical sciences; Pharmacology/Toxicology; Phosphorylation; Proteins; Rats; Reactive oxygen species; Sirtuin 3 - metabolism; Therapeutic targets; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-022-00966-8

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 K d value of 15 μM, and increased SIRT3 deacetylation activity with EC 50 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.