FABP4 silencing ameliorates hypoxia reoxygenation injury through the attenuation of endoplasmic reticulum stress-mediated apoptosis by activating PI3K/Akt pathway.

Endoplasmic reticulum (ER) stress and subsequent apoptosis play a vital role in myocardial ischemia reperfusion (IR) injury. Fatty acid binding protein 4 (FABP4) may induce ER stress. The aim of this study was to investigate the mechanism and effect of FABP4 on IR injury in vitro. Rat H9c2 cells were exposed to hypoxia reoxygenation (HR) to create an IR model in vitro. FABP4 was overexpressed in HR-injured H9c2 cells. Transfection with FABP4 siRNA increased cell viability and decreased LDH upon HR stimulation. FABP4 cessation also suppressed apoptotic cells and caspase-3 activity after HR. Downregulation of FABP4 significantly inhibited ER stress by decreasing the protein expression of p-PERK, GRP78, and ATF6. FABP4 silencing also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins p-JNK, CHOP, Bax, and caspase-12, as well as upregulation of Bcl-2 during HR. Furthermore, FABP4 silencing activated the PI3K/Akt pathway. Blocking this pathway by the specific PI3K inhibitor-LY294002 restored HR-induced ER stress and subsequently reversed the protective effect of FABP4 silencing on HR injury. Taken together, our findings revealed that FABP4 silencing exerts protective effects against HR injury in H9c2 cells through inhibiting ER stress-induced cell apoptosis via activation of the PI3K/Akt pathway.

Deng T ，Wang Y ，Wang C ，Yan H ... -  《-》

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.

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. 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. 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. 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. 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. 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.

Yu Y ，Xing N ，Xu X ，Zhu Y ，Wang S ，Sun G ，Sun X ... -  《-》

Glucagon-like peptide-1 attenuates endoplasmic reticulum stress-induced apoptosis in H9c2 cardiomyocytes during hypoxia/reoxygenation through the GLP-1R/PI3K/Akt pathways.

Guan G ，Zhang J ，Liu S ，Huang W ，Gong Y ，Gu X ... -  《-》

Cardioprotective effects of dihydroquercetin against ischemia reperfusion injury by inhibiting oxidative stress and endoplasmic reticulum stress-induced apoptosis via the PI3K/Akt pathway.

Shu Z ，Yang Y ，Yang L ，Jiang H ，Yu X ，Wang Y ... -  《-》

Nerve growth factor protects the ischemic heart via attenuation of the endoplasmic reticulum stress induced apoptosis by activation of phosphatidylinositol 3-kinase.

Wei K ，Liu L ，Xie F ，Hao X ，Luo J ，Min S ... -  《International Journal of Medical Sciences》