title: Lipid emulsion reverses bupivacaine-induced apoptosis of h9c2 cardiomyocytes: PI3K/Akt/GSK-3β signaling pathway.
abstract: Some findings have suggested that the rescue of bupivacaine (BPV)-induced cardiotoxicity by lipid emulsion (LE) is associated with inhibition of mitochondrial permeability transition pore (mPTP). However, the mechanism of this rescue action is not clearly known. In this study, the roles of phosphoinositide 3-kinase (PI3K)/Akt and glycogen synthase kinase-3β (GSK-3β) in the molecular mechanism of LE-induced protection and its relationship with mPTP were explored. h9c2 cardiomyocytes were randomly divided into several groups: control, BPV, LE, BPV+LE. To study the effect of LE on mPTP, atractyloside (Atr, 20 μM, mPTP opener) and cyclosporine A (CsA, 10 μM, mPTP blocker) were used. To unravel whether LE protects heart through the PI3K/Akt/GSK-3β signaling pathway, cells were treated with LY294002 (LY, 30 μM, PI3K blocker) or TWS119 (TWS 10 μM, GSK-3β blocker). Later mitochondrial respiratory chain complexes, apoptosis, opening of mPTP and phosphorylation levels of Akt/GSK-3β were measured. LE significantly improved the mitochondrial functions in h9c2 cardiomyocytes. LE reversed the BPV-induced apoptosis and the opening of mPTP. The effect of LE was not only enhanced by CsA and TWS, but also abolished by Atr and LY. LE also increased the phosphorylation levels of Akt and GSK-3β. These results suggested that LE can reverse the apoptosis in cardiomyocytes by BPV and a mechanism of its action is inhibition of mPTP opening through the PI3K/Akt/GSK-3β signaling pathway.
authors.affiliation: Ning Xia Medical University, Yin Chuan, China. Electronic address: lvdanni19890216@163.com.
authors.forename: Danni
authors.initials: D
authors.lastname: Lv
authors.affiliation: Department of Anesthesiology, Tumor Hospital, General Hospital of Ning Xia Medical University, Yin Chuan, China. Electronic address: zx4073354@163.com.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Bai
authors.affiliation: Department of Anesthesiology, First People's Hospital, Shi Zui Shan, China. Electronic address: yanglibing1984@163.com.
authors.forename: Libin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Ning Xia Medical University, Yin Chuan, China. Electronic address: crystalliy@163.com.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Tumor Hospital, General Hospital of Ning Xia Medical University, Yin Chuan, China. Electronic address: chenxuexin2637@163.com.
authors.forename: Xuexin
authors.initials: X
authors.lastname: Chen
mesh_terms: D002045:Bupivacaine / Q000633:toxicity*; D054715:Cardiotoxins / Q000633:toxicity*; D000071679:Glycogen Synthase Kinase 3 beta; D008055:Lipids / Q000494:pharmacology*; D008928:Mitochondria; D033681:Mitochondrial Membrane Transport Proteins; D051336:Mitochondrial Membranes; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases; D015398:Signal Transduction
chemical_list: D002045:Bupivacaine; D054715:Cardiotoxins; D000071679:Glycogen Synthase Kinase 3 beta; D008055:Lipids; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019869:Phosphatidylinositol 3-Kinases
keywords: Bupivacaine; Cardiac cytotoxicity; Lipid emulsion; PI3K/Akt/GSK-3β; mPTP