High content screening identifies licoisoflavone A as a bioactive compound of Tongmaiyangxin Pills to restrain cardiomyocyte hypertrophy via activating Sirt3

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL
Rui Guo , Ningning Liu , Hao Liu , Junhua Zhang , Han Zhang , Yingchao Wang , Mirko Baruscotti , Lu Zhao , Yi Wang
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引用次数: 8

Abstract

Background

: Cardiac hypertrophy is a prominent feature of heart remodeling, which may eventually lead to heart failure. Tongmaiyangxin (TMYX) pills are a clinically used botanical drug for treating multiple cardiovascular diseases including chronic heart failure. The aim of the current study was to identify the bioactive compounds in Tongmaiyangxin pills that attenuate cardiomyocytes hypertrophy, and to investigate the underlying mechanism of action.

Methods and Results

: The anti-hypertrophy effect of TMYX was validated in isoproterenol-induced cardiac hypertrophy model in C57BL/6 mice. After TMYX treatment for 2 weeks, the heart ejection fraction and fractional shortening of the mice model was increased by approximately 20% and 15%, respectively, (p < 0.05). Besides, TMYX dose-dependently reduced the cross section area of cardiomyocytes in the angiotensin-II induced hypertrophy H9c2 model (p < 0.01). Combining high content screening and liquid chromatography mass spectrometry, four compounds with anti-cardiac hypertrophy effects were identified from TMYX, which includes emodin, licoisoflavone A, licoricone and glyasperin A. Licoisoflavone A is one of the compounds with most significant protective effect and we continued to investigate the mechanism. Primary cultures of neonatal rat cardiomyocytes were treated with a hypertrophic agonist phenylephrine (PE) in the presence or absence of licoisoflavone A. After 48 h of treatment, cells were harvested and mitochondrial acetylation was analyzed by western blotting and Image analysis. Interestingly, the results suggested that the anti-hypertrophic effects of licoisoflavone A depend on the activation of the deacetylase Sirt3 (p < 0.01). Finally, we showed that licoisoflavone A-treatment was able to decrease relative ANF and BNP levels in the hypertrophic cardiac cells (p < 0.01), but not in cells co-treated with Sirt3 inhibitors (3-TYP) (p > 0.05).

Conclusion

: TMYX exerts its anti-hypertrophy effect possibly through upregulating Sirt3 expression. Four compounds were identified from TMYX which may be responsible for the anti-hypertrophy effect. Among these compounds, licoisoflavone A was demonstrated to block the hypertrophic response of cardiomyocytes, which required its positive regulation on the expression of Sirt3. These results suggested that licoisoflavone A is a potential Sirt3 activator with therapeutic effect on cardiac hypertrophy.

Abstract Image

高含量筛选鉴定通脉养心丸中甘草异黄酮A是通过激活Sirt3抑制心肌细胞肥大的活性物质
背景:心脏肥厚是心脏重构的一个显著特征,最终可能导致心力衰竭。通脉养心(TMYX)丸是临床上用于治疗包括慢性心力衰竭在内的多种心血管疾病的植物性药物。本研究旨在鉴定通脉养心丸中具有减轻心肌细胞肥厚作用的活性成分,并探讨其作用机制。方法与结果:在异丙肾上腺素诱导的C57BL/6小鼠心肌肥厚模型中验证了TMYX的抗肥厚作用。TMYX治疗2周后,小鼠模型心脏射血分数和分数缩短分别增加约20%和15%,(p <0.05)。此外,TMYX剂量依赖性地减少了血管紧张素ii诱导的肥厚H9c2模型中心肌细胞的横截面积(p <0.01)。结合高含量筛选和液相色谱质谱分析,从TMYX中鉴定出4种具有抗心肌肥厚作用的化合物,分别为大黄素、甘草异黄酮A、甘草异黄酮和glyasperin A。其中,甘草异黄酮A的保护作用最为显著,我们将继续探讨其作用机制。用肥厚激动剂苯肾上腺素(PE)处理新生大鼠心肌细胞原代培养物,在存在或不存在licoisoflavone a的情况下处理48小时后,收集细胞,通过western blotting和图像分析分析线粒体乙酰化。有趣的是,结果表明,甘草异黄酮A的抗肥厚作用依赖于去乙酰化酶Sirt3的激活(p <0.01)。最后,我们发现licoisoflavone a处理能够降低肥大心肌细胞中ANF和BNP的相对水平(p <0.01),但在与Sirt3抑制剂(3-TYP)共处理的细胞中没有(p >0.05)。结论:TMYX可能通过上调Sirt3表达发挥其抗肥厚作用。从TMYX中鉴定出四种可能与抗肥厚作用有关的化合物。在这些化合物中,licoisoflavone A被证明可以阻断心肌细胞的肥厚反应,这需要其对Sirt3表达的正向调节。这些结果提示licoisoflavone A是一种潜在的Sirt3激活剂,具有治疗心肌肥厚的作用。
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来源期刊
Phytomedicine
Phytomedicine 医学-药学
CiteScore
10.30
自引率
5.10%
发文量
670
审稿时长
91 days
期刊介绍: Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.
文献相关原料
公司名称 产品信息 采购帮参考价格
上海源叶 Licoricone
¥3490.00~¥23500.00
阿拉丁 Angiotensin II (Ang II)
¥39.00~¥21411.00
上海源叶 Licorisoflavan A
¥3427.00~¥8000.00
上海源叶 Glycycoumarin
¥265.00~¥6272.00
上海源叶 Glyasperin A
¥3630.00~¥5760.00
上海源叶 Glycyrol
¥333.00~¥4190.00
上海源叶 Licoisoflavone A
上海源叶 Licoisoflavone A
阿拉丁 Phenylephrine (PE)
阿拉丁 Isoprenaline hydrochloride (ISO)
阿拉丁 Phenylephrine (PE)
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