SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice
SZC-6, a small-molecule activator of SIRT3, attenuates cardiac hypertrophy in mice
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SZC-6 是 SIRT3 的小分子激活剂，可减轻小鼠心脏肥大
DOI：
10.1038/s41401-022-00966-8
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发表时间：
2022-08-30
影响因子：
8.2
通讯作者：
Liu, Pei-qing
中科院分区：
文献类型：
--
作者：
Li, Ze-yu;Lu, Guo-qing;Liu, Pei-qing
Sirtuin 3（SIRT 3）是一种III类组蛋白去乙酰化酶，作为一种新的治疗靶点与多种心血管疾病有关。SIRT 3已被证明在Ang II诱导的心脏肥大模型中具有心脏保护作用。然而，一些靶向脱乙酰酶的小分子化合物可以激活SIRT 3。在这项研究中，我们通过第一个SIRT 3激动剂C12的结构优化产生了一种新的SIRT 3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直接结合SIRT 3，Kd值为15 μ M，并增加SIRT 3脱乙酰化活性，EC 50值为23.2 +/- 3.3 μ M。在新生大鼠心肌细胞（NRCMs），预处理与SZC-6（10，20，40 μ M）剂量依赖性衰减异丙肾上腺素（ISO）诱导的肥大反应。SZC-6（20、40和60 mg中心点kg（-1）中心点d（，）（-1）s.c.）从ISO处理前一周开始持续2周，在野生型小鼠中剂量依赖性地逆转ISO诱导的舒张和收缩心脏功能的损害，但在SIRT 3敲低小鼠中不逆转。我们发现，SZC-6（10，20，40 μ M）剂量依赖性地抑制心脏成纤维细胞增殖和分化成肌成纤维细胞，这是取消在SIRT 3敲低小鼠。我们进一步揭示了SZC-6对SIRT 3的激活增加了ATP的产生和线粒体耗氧速率，并减少了ROS，改善了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LKB 1磷酸化，从而促进AMPK激活，抑制Drp 1依赖的线粒体片段化。综上所述，这些结果表明SZC-6是一种新型SIRT 3激动剂，部分通过激活LKB 1-AMPK通路在治疗心脏肥大中具有潜在价值。
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 mu M, and increased SIRT3 deacetylation activity with EC50 value of 23.2 +/- 3.3 mu M. In neonatal rat cardiomyocytes (NRCMs), pretreatment with SZC-6 (10, 20, 40 mu M) dose-dependently attenuated isoproterenol (ISO)-induced hypertrophic responses. Administration of SZC-6 (20, 40 and 60 mg center dot kg(-1)center dot 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 mu M) 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.