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

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(max), - dP/dt(min), 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 eIf2 alpha. 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.