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

Authors: Zhen-dong Xu1,2, Yong Wang1,3, Ge Liang1, Zhi-qiang Liu2, Wu-hua Ma3, Charleen T Chu4, Hua-feng Wei1
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
Correspondence to: Hua-feng Wei: weih@uphs.upenn.edu,
DOI: 10.1038/s41401-019-0303-z
Received: 12 April 2019
Accepted: 29 August 2019
Advance online: 23 October 2019

Abstract

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 (10 µM), but caused cell death at an extremely high concentration (200 µM) in ATG5−/− MEF, but not in WT cells. The dual effects found in ATG5−/− MEF could be blocked by intracellular Ca2+ channel antagonists. We also found that propofol evoked a moderate (promote cell growth) and extremely high (cause apoptosis) cytosolic Ca2+ elevation at the concentrations of 10 µM and 200 µM, respectively, only in ATG5−/− MEF. In addition, ATG5−/− MEF themselves released more Ca2+ 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 Ca2+ homeostasis.
Keywords: propofol; autophagy; ATG5; calcium; InsP3 receptors; ryanodine receptors; mouse embryonic fibroblasts

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