Yingli Yu1, Na Xing2, Xudong Xu3, Yindi Zhu4, Shan Wang1, Guibo Sun5, Xiaobo Sun6. 1. 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. 2. Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Harbin 150040, China. 3. 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. 4. School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, PR China. 5. 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. Electronic address: sunguibo@126.com. 6. 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. Electronic address: sun_xiaobo163@163.com.
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/dtmax, - dP/dtmin, 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.
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/dtmax, - dP/dtmin, 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.