旋覆花酸 B 来源于荆芥（Benth.）Kuntze，通过抑制内质网应激调节的凋亡途径 PI3K/AKT 来保护心肌缺血/再灌注损伤。

Tournefolic acid B, derived from Clinopodium chinense (Benth.) Kuntze, protects against myocardial ischemia/reperfusion injury by inhibiting endoplasmic reticulum stress-regulated apoptosis via PI3K/AKT pathways.

机构信息

Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China; Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing 100193, China; Zhongguancun Open Laboratory of the Research and Development of Natural Medicine and Health Products, Beijing 100193, China; Key Laboratory of the efficacy evaluation of Chinese Medicine against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China.

Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Harbin 150040, China.

出版信息

Phytomedicine. 2019 Jan;52:178-186. doi: 10.1016/j.phymed.2018.09.168. Epub 2018 Oct 2.

DOI:10.1016/j.phymed.2018.09.168

PMID:30599897

Abstract

BACKGROUND

Protection the heart from ischemia/reperfusion (I/R) injury is an area of intense research, as myocardial infarction is a major cause of mortality and morbidity all around the world. Tournefolic acid B (TAB) is a relative new compound derived from Clinopodium chinense (Benth.) Kuntze (Chinese name: Feng Lun Cai). This traditional Chinese herbal medicine has been used for its activities on anti-inflammatory, lowering blood glucose, antitumor and antiradiation. However, the pharmacological effects of TAB were rarely studied.

PURPOSE

Pathways involving phosphoinositide 3-kinase (PI3K) and protein kinase b (Akt) are crucial in regulating the ER stress and associated apoptosis in the process of I/R injury. In the present study, we aim to investigate the cardioprotective effects of tournefolic acid B (TAB) against myocardial I/R injury and explore the molecular mechanisms involved.

STUDY DESIGN

H9c2 cadiomyocyte were incubated with TAB for 24 h and then exposed to hypoxia/reoxygenation. Isolated rat hearts were subjected to global ischemia and reperfusion in the absence or presence of TAB.

METHODS

The possible mechanisms were investigated in vitro and ex vivo by multiple detection methods including JC-1 staining, ROS detection, activities of caspases detection, TUNEL staining, and Western-blot analysis.

RESULTS

We found that TAB significantly improved the hemodynamic parameters (LVeDP, LVSP, + dP/dt, - dP/dt, and HR) of isolated rat hearts, and depressed the cardiomyocyte apoptosis. Besides, TAB inhibited the oxidative stress by adjusting the activities of antioxidant enzymes (SOD, CAT, and GSH-Px). The I/R injury triggered the endoplasmic reticulum (ER) stress by activating the ER proteins, such as Grp78, ATF6, PERK, and eIf2α. which are all refrained by TAB. TAB also enhanced the phosphorylation of PI3K and AKT, inhibited the expression of CHOP and Caspase-12, reduced the phosphorylation of JNK, and increased Bcl-2/Bax ratio.

CONCLUSION

TAB protects against myocardial I/R injury by suppressing PI3K/AKT-mediated ER stress, oxidative stress, and apoptosis, revealing a promising therapeutic agent against ischemic cardiovascular diseases.

摘要

背景

保护心脏免受缺血/再灌注（I/R）损伤是一个研究热点，因为心肌梗死是全世界死亡率和发病率的主要原因。Tournefolic 酸 B（TAB）是一种从唇形科荆芥（Benth.）Kuntze（中文名：风铃草）中衍生出来的相对较新的化合物。这种传统中药因其具有抗炎、降血糖、抗肿瘤和抗辐射作用而被使用。然而，TAB 的药理作用很少被研究。

目的

涉及磷酸肌醇 3-激酶（PI3K）和蛋白激酶 b（Akt）的途径在调节 I/R 损伤过程中的内质网应激和相关凋亡中至关重要。在本研究中，我们旨在研究 Tournefolic 酸 B（TAB）对心肌 I/R 损伤的保护作用，并探讨涉及的分子机制。

研究设计

H9c2 心肌细胞用 TAB 孵育 24 小时，然后暴露于缺氧/复氧中。在不存在或存在 TAB 的情况下，将分离的大鼠心脏进行整体缺血和再灌注。

方法

通过 JC-1 染色、ROS 检测、半胱天冬酶活性检测、TUNEL 染色和 Western-blot 分析等多种检测方法，在体外和体内研究可能的机制。

结果

我们发现 TAB 显著改善了分离大鼠心脏的血流动力学参数（LVeDP、LVSP、+dp/dt、-dp/dt 和 HR），并抑制了心肌细胞凋亡。此外，TAB 通过调节抗氧化酶（SOD、CAT 和 GSH-Px）的活性来抑制氧化应激。I/R 损伤通过激活内质网（ER）蛋白（如 Grp78、ATF6、PERK 和 eIf2α）来触发 ER 应激，而这些都被 TAB 抑制。TAB 还增强了 PI3K 和 AKT 的磷酸化，抑制了 CHOP 和 Caspase-12 的表达，降低了 JNK 的磷酸化，并增加了 Bcl-2/Bax 比值。