National-Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Province Engineering Laboratoty for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
Acta Pharmacol Sin. 2023 Mar;44(3):546-560. doi: 10.1038/s41401-022-00966-8. Epub 2022 Aug 30.
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 value of 15 μM, and increased SIRT3 deacetylation activity with EC 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·d 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.
Sirtuin3（SIRT3）是一种 III 类组蛋白去乙酰化酶，作为一种新的治疗靶点，它与各种心血管疾病有关。在 Ang II 诱导的心肌肥厚模型中，SIRT3 已被证明具有心脏保护作用。然而，一些靶向去乙酰化酶的小分子化合物可以激活 SIRT3。在这项研究中，我们通过对第一个 SIRT3 激动剂 C12 的结构优化，生成了一种新型的 SIRT3 激活剂 3-(2-溴-4-羟基苯基)-7-羟基-2H-色烯-2-酮（SZC-6）。我们证明 SZC-6 以 15μM 的 K 值直接与 SIRT3 结合，并以 23.2±3.3μM 的 EC 值增加 SIRT3 的脱乙酰化活性。在新生大鼠心肌细胞（NRCMs）中，SZC-6（10、20、40μM）预处理剂量依赖性地减弱异丙肾上腺素（ISO）诱导的心肌肥厚反应。从 ISO 处理前一周开始，SZC-6（20、40 和 60mg·kg·d 皮下注射）连续 2 周给药，剂量依赖性地逆转了野生型小鼠 ISO 诱导的舒张和收缩性心脏功能障碍，但在 SIRT3 敲低小鼠中没有。我们表明，SZC-6（10、20、40μM）剂量依赖性地抑制心肌成纤维细胞增殖和分化为肌成纤维细胞，而在 SIRT3 敲低小鼠中则被消除。我们进一步揭示，SZC-6 激活 SIRT3 可增加 ATP 产生和线粒体耗氧量，并减少 ROS，改善 ISO 处理的 NRCM 中的线粒体功能。我们还发现，SZC-6 剂量依赖性地增强 LKB1 磷酸化，从而促进 AMPK 激活以抑制 Drp1 依赖性线粒体片段化。总之，这些结果表明 SZC-6 是一种新型的 SIRT3 激动剂，具有通过激活 LKB1-AMPK 通路治疗心肌肥厚的潜力。
