CN113616640A - 欧当归内酯a在制备抗心梗后心室重构的药物中用途 - Google Patents

欧当归内酯a在制备抗心梗后心室重构的药物中用途 Download PDF

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CN113616640A
CN113616640A CN202110956323.8A CN202110956323A CN113616640A CN 113616640 A CN113616640 A CN 113616640A CN 202110956323 A CN202110956323 A CN 202110956323A CN 113616640 A CN113616640 A CN 113616640A
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levistilide
myocardial infarction
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张竞之
刘彬
谭章斌
徐由财
丁文俊
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Abstract

本发明提供了欧当归内酯A在制备抗心梗后心室重构的药物中用途，欧当归内酯A对正常细胞的毒性低，来源于传统中药当归、川芎，具有一定安全性，而且制备成本亦较低，可作为一种有前景的抗心梗后心室重构药物。

Description

欧当归内酯A在制备抗心梗后心室重构的药物中用途
技术领域
本发明涉及欧当归内酯A在制备抗心梗后心室重构的药物中用途。
背景技术
目前ACEI、ARB等防治心梗后心室重构的疗效已被大量循证医学研究证实，并写入治疗指南。然而我们必须看到尽管使用了ACEI、ARB，甚至多种药物联用，慢性心衰的住院率和死亡率仍持续走高，5年死亡率高达50％，心室重构仍沿着目前未知的机制发展至心衰。因此深入探索心梗后心室重构的确切发病机制和有效药物，无疑对防治心梗后心室重构有重要的理论意义和实用价值。以后的研究证实心肌梗死后心肌压力超负荷刺激心肌组织分泌RAAS系统成分是产生和促进心梗后心室重构的重要神经内分泌途径。而在此途径中RAAS系统的核心物质，血管紧张素Ⅱ(angiotensinⅡ)的分泌则发挥着关键性的作用。因此，阻断AngⅡ成为抑制重构的最佳药物。
AT1受体(Angiotensin II type 1receptor,AT1R)是一种膜受体，它具有激素受体的所有特征。它介导血管紧张素Ⅱ受体的所有病理生理功能，包括平滑肌收缩，醛固酮、儿茶酚胺和精氨酚释放，调节液体量和促进细胞增殖等。
欧当归内酯A(Levistilide A)是中药当归、川芎的主要活性成分之一。当归、川芎是临床上最常见的活血类中药，目前报道具有心血管保护作用及抗纤维化等作用。目前没有欧当归内酯A治疗心梗后心室重构的相关报道，以及未见报道其与AT1受体的关系。
目前ACEI、ARB等防治心梗后心室重构的疗效已被大量循证医学研究证实，并写入治疗指南。然而我们必须看到尽管使用了ACEI、ARB，甚至多种药物联用，慢性心衰的住院率和死亡率仍持续走高，5年死亡率高达50％，心室重构仍沿着目前未知的机制发展至心衰。因此深入探索心梗后心室重构的确切发病机制和有效药物，无疑对防治心梗后心室重构有重要的理论意义和实用价值。
发明内容
本发明的目的在于提供欧当归内酯A在制备抗心梗后心室重构的药物中用途，欧当归内酯A可以降低AT1受体的活性，能够用于防治心梗后心室重构，满足人们的需要。
为实现上述目的，所采取的技术方案：本发明提供了欧当归内酯A在制备抗心梗后心室重构的药物中用途。
有益效果：
欧当归内酯A对正常细胞的毒性低，来源于传统中药当归、川芎，具有一定安全性，而且制备成本亦较低，可作为一种有前景的抗心梗后心室重构药物。
附图说明
图1为欧当归内酯A抑制AngII诱导心肌成纤维细胞增殖的图片，其中(A)欧当归内酯A对心肌细胞活性的影响；(B)欧当归内酯A对AngII诱导心肌成纤维细胞增殖的影响。注：**P＜0.05VS Model。
图2为欧当归内酯A对AngII诱导心肌成纤维细胞AT1R表达的影响，其中(A)欧当归内酯A对AngII诱导心肌成纤维细胞AT1R表达的影响；(B)AT1R相对表达量。注：**P＜0.05VSModel。
图3为AT1R-欧当归内酯A络合物的三维晶体结构。
图4为欧当归内酯A与AT1R结合分子动力学模拟结果，其中A：20ns后表面可视化模型；B：重原子均方根偏差(RMSD)变化曲线。
图5为不同浓度的欧当归内酯A(10μM、20μM和40μM)对AT1R的表面等离子共振拟合曲线，表面等离子共振信号以共振单位(RU)表示。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
本发明发现欧当归内酯A体外可以降低AT1R激酶的活性，该效应具有浓度依赖性；基于计算机模拟辅助筛选技术分子对接及分子动力学揭示欧当归内酯A在空间上能够稳定的结合AT1R激酶的活性区域，结合表面等离子共振实验的结果，其可能是一种天然的AT1R激酶抑制剂。进一步的，发现欧当归内酯A做为防治心梗后心室重构药物的应用。
本发明涉及的欧当归内酯A的分子式为C24H28O4，分子量380.48。
实施例1欧当归内酯A抑制AngII诱导心肌成纤维细胞增殖
我们先探索不同剂量欧当归内酯A对心肌细胞活性的影响以选择无毒性的剂量，我们发现欧当归内酯A在大于100μM有一定的毒性(如图1A)。因此，我们选择10、20、40μM的有效成分用于后续试验。我们发现AngII显著提高心肌成纤维细胞的细胞活力，与对照组比较差异有统计学意义，不同剂量的欧当归内酯A能浓度依赖性地降低AngII诱导的细胞活力升高，与AngII组比较差异有统计学意义(如图1B)。
实施例2欧当归内酯A抑制AngII诱导心肌成纤维细胞AT1R表达
我们进一步探讨欧当归内酯A对AngII诱导心肌成纤维细胞AT1R表达的影响。结果如图2显示，AngII显著提高心肌成纤维细胞的细胞AT1R的表达，与对照组比较差异有统计学意义，不同剂量的欧当归内酯A能降低AngII诱导的AT1R表达升高，与AngII组比较差异有统计学意义。
实施例3分子对接和分子动力学模拟探索AT1R-欧当归内酯A的相互作用我们首先采用分子对接技术进行分析，结果表明AT1R和欧当归内酯A(MOL002200)之间的结合能为-10.349kcal/mol。AT1R-欧当归内酯A络合物的三维晶体结构如图3所示。接着通过分子动力学模拟，进一步研究了AT1R-欧当归内酯A复合物的稳定性。AT1R-欧当归内酯A复合物在0ns和20ns处的表面可视化模型如图4A所示。由结果可见，欧当归内酯A稳定地呈现在AT1R结合位点的中心，直到MD模拟结束。图4B显示了重原子均方根偏差(RMSD)的演变。AT1R的全部原子RMSD轨迹波动在
Figure BDA0003220420230000031
之间。配体欧当归内酯A的全部原子RMSD轨迹稳定波动在
Figure BDA0003220420230000032
左右。以上这些结果表明AT1R与欧当归内酯A的结合是稳定的。
实施例4表面等离子共振探索AT1R-欧当归内酯A的结合作用
表面等离子共振分析表明欧当归内酯A可以以浓度依赖的方式快速结合AT1R，平衡解离常数(KD)值为1.07×10-8M。平衡解离常数的结果表明欧当归内酯A对AT1R具有很强的亲和力，提示欧当归内酯A能与AT1R的直接结合(图5)。
通过上述一系列实验最终得出结论：欧当归内酯A能浓度依赖性地抑制AT1R的激活，与AT1R有着较强的结合能力，具有稳定的结合性，可能是一种天然的新型AT1R抑制剂。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

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1.欧当归内酯A在制备抗心梗后心室重构的药物中用途。
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CN102772400A (zh) * 2012-01-12 2012-11-14 上海中医药大学 欧当归内酯a的医药用途
CN112852733A (zh) * 2021-01-19 2021-05-28 南开大学 欧当归内酯a在制备人造血干细胞体外扩增的药物中的用途
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CN102631387A (zh) * 2012-04-24 2012-08-15 天津大学 一种治疗心脑血管病的川芎内酯类成分制剂及其制备方法
WO2021114125A1 (zh) * 2019-12-11 2021-06-17 辽宁双士利医药科技有限公司 欧当归内酯a在制备治疗或预防肾病药物中的用途
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