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High content screening identifies licoisoflavone A as a bioactive compound of Tongmaiyangxin Pills to restrain cardiomyocyte hypertrophy via activating Sirt3.
Phytomedicine ( IF 6.7 ) Pub Date : 2020-01-17 , DOI: 10.1016/j.phymed.2020.153171 Rui Guo 1 , Ningning Liu 2 , Hao Liu 1 , Junhua Zhang 3 , Han Zhang 3 , Yingchao Wang 1 , Mirko Baruscotti 4 , Lu Zhao 1 , Yi Wang 1
Phytomedicine ( IF 6.7 ) Pub Date : 2020-01-17 , DOI: 10.1016/j.phymed.2020.153171 Rui Guo 1 , Ningning Liu 2 , Hao Liu 1 , Junhua Zhang 3 , Han Zhang 3 , Yingchao Wang 1 , Mirko Baruscotti 4 , Lu Zhao 1 , Yi Wang 1
Affiliation
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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.
中文翻译：
高含量的筛选确定了异黄酮A是通脉养心丸的一种生物活性化合物，可通过激活Sirt3抑制心肌肥大。
背景技术心脏肥大是心脏重塑的突出特征，其最终可能导致心力衰竭。Tongmaiyangxin（TMYX）药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药。本研究的目的是鉴定通脉养心丸中能减轻心肌肥大的生物活性化合物，并研究其潜在的作用机理。方法和结果在异丙肾上腺素诱发的C57BL / 6小鼠心脏肥大模型中验证了TMYX的抗肥大作用。在TMYX治疗2周后，小鼠模型的心脏射血分数和缩短分数分别增加了约20％和15％（p <0.05）。除了，在血管紧张素II引起的肥大性H9c2模型中，TMYX剂量依赖性地减少了心肌细胞的横截面积（p <0.01）。结合高含量筛查和液相色谱质谱法，从TMYX中鉴定出四种具有抗心肌肥大作用的化合物，包括大黄素，异黄酮A，licoricone和glyasperinA。异黄酮A是最具保护作用的化合物之一，我们继续调查机制。在存在或不存在异黄酮A的情况下，用肥大性激动剂去氧肾上腺素（PE）处理新生大鼠心肌的原代培养物。处理48小时后，收获细胞，并通过蛋白质印迹和图像分析对线粒体乙酰化进行分析。有趣的是 结果表明，异黄酮A的抗肥大作用取决于脱乙酰基酶Sirt3的激活（p <0.01）。最后，我们表明，异黄酮A处理能够降低肥厚性心肌细胞的相对ANF和BNP水平（p <0.01），但不能与Sirt3抑制剂（3-TYP）共同处理的细胞（p> 0.05）。结论TMYX可能通过上调Sirt3表达发挥其抗肥大作用。从TMYX鉴定出四种化合物可能是抗肥大作用的原因。在这些化合物中，柠檬黄酮A被证明可以阻断心肌细胞的肥大反应，这需要其对Sirt3表达的积极调节。
更新日期：2020-01-17
中文翻译：
高含量的筛选确定了异黄酮A是通脉养心丸的一种生物活性化合物，可通过激活Sirt3抑制心肌肥大。
背景技术心脏肥大是心脏重塑的突出特征，其最终可能导致心力衰竭。Tongmaiyangxin（TMYX）药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药。本研究的目的是鉴定通脉养心丸中能减轻心肌肥大的生物活性化合物，并研究其潜在的作用机理。方法和结果在异丙肾上腺素诱发的C57BL / 6小鼠心脏肥大模型中验证了TMYX的抗肥大作用。在TMYX治疗2周后，小鼠模型的心脏射血分数和缩短分数分别增加了约20％和15％（p <0.05）。除了，在血管紧张素II引起的肥大性H9c2模型中，TMYX剂量依赖性地减少了心肌细胞的横截面积（p <0.01）。结合高含量筛查和液相色谱质谱法，从TMYX中鉴定出四种具有抗心肌肥大作用的化合物，包括大黄素，异黄酮A，licoricone和glyasperinA。异黄酮A是最具保护作用的化合物之一，我们继续调查机制。在存在或不存在异黄酮A的情况下，用肥大性激动剂去氧肾上腺素（PE）处理新生大鼠心肌的原代培养物。处理48小时后，收获细胞，并通过蛋白质印迹和图像分析对线粒体乙酰化进行分析。有趣的是 结果表明，异黄酮A的抗肥大作用取决于脱乙酰基酶Sirt3的激活（p <0.01）。最后，我们表明，异黄酮A处理能够降低肥厚性心肌细胞的相对ANF和BNP水平（p <0.01），但不能与Sirt3抑制剂（3-TYP）共同处理的细胞（p> 0.05）。结论TMYX可能通过上调Sirt3表达发挥其抗肥大作用。从TMYX鉴定出四种化合物可能是抗肥大作用的原因。在这些化合物中，柠檬黄酮A被证明可以阻断心肌细胞的肥大反应，这需要其对Sirt3表达的积极调节。
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