Propofol affects mouse embryonic fibroblast survival and proliferation in vitro via ATG5- and calcium-dependent regulation of autophagy  

作　　者：Zhen-dong Xu Yong Wang Ge Liang Zhi-qiang Liu Wu-hua Ma Charleen T Chu Hua-feng Wei 

机构地区：[1]Department of Anesthesiology and Critical Care,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA 19104,USA [2]Department of Anesthesiology,Shanghai First Maternity and Infant Hospital,Tongji University School of Medicine,Shanghai 201204,China [3]Department of Anesthesiology,The First Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510545,China [4]Department of Pathology,Division of Neuropathology,University of Pittsburgh School of Medicine,Pittsburgh,PA 15261,USA

出　　处：《Acta Pharmacologica Sinica》2020年第3期303-310,共8页中国药理学报（英文版）

基　　金：Supported by grants to HW from the NIH(R01GM084979,3R01GM084979-02S1,and 2R01GM084979-06A1)and R01AG026389-10S1 to CTC;Supported by grants to ZX from Shanghai Municipal Health Bureau(201840149);Supported by grants to ZX from the National Natural Science Foundation of China(81971418);Supported by grants to YW from the National Natural Science Foundation of China(81503663).

摘　　要：Propofol is a commonly used intravenous anesthetic agent,which has been found to affect cell survival and proliferation especially in early life.Our previous studies show that propofol-induced neurodegeneration and neurogenesis are closely associated with cell autophagy.In the present study we explored the roles of autophagy-related gene 5(ATG5)in propofol-induced autophagy in mouse embryonic fibroblasts(MEF)in vitro.We showed that ATG5 was functionally related to propofol-induced cell survival and damage:propofol significantly enhanced cell survival and proliferation at a clinically relevant dose(10μM),but caused cell death at an extremely high concentration(200μM)in ATG5^-/-MEF,but not in WT cells.The dual effects found in ATG5^-/-MEF could be blocked by intracellular Ca^2+channel antagonists.We also found that propofol evoked a moderate(promote cell growth)and extremely high(cause apoptosis)cytosolic Ca^2+elevation at the concentrations of 10μM and 200μM,respectively,only in ATG5^-/-MEF.In addition,ATG5^-/-MEF themselves released more Ca^2+in cytosolic space and endoplasmic reticulum compared with WT cells,suggesting that autophagy deficiency made intracellular calcium signaling more vulnerable to external stimuli(propofol).Altogether,our results reveal that ATG5 plays a crucial role in propofol regulation of cell survival and proliferation by affecting intracellular Ca^2+homeostasis.

关 键 词：PROPOFOL AUTOPHAGY ATG5 CALCIUM lnsP3 RECEPTORS RYANODINE RECEPTORS mouse embryonic FIBROBLASTS 

分 类 号：R285.5[医药卫生—中药学]