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

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 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 10 µM and 200 µM, 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.

Crucial role of autophagy in propofol-treated neurological diseases: a comprehensive review

“…However, clinically relevant doses of propofol can promote the proliferation of NPC cells and increase the differentiation of neurons. Similar to the findings reported Qiao et al (2017) and Xu et al (2020) demonstrated that dose-dependent propofol affects the proliferation and death of mouse fibroblasts in vitro via regulation of autophagy by affecting calcium release, and AGT5 plays an important role in this process. More importantly, the cells with Alzheimer’s disease characteristics were more susceptible to propofol neurotoxicity ( Xie et al, 2007 ).…”

Anaesthesia and brain development: a review of propofol-induced neurotoxicity in pediatric populations

“…30 In mouse embryonic fibroblasts, it was also found that propofol caused a large outflow of Ca 2+ in the endoplasmic reticulum and thus cell death. 31 Therefore, calcium overload is closely related to the neurotoxicity of propofol. These findings may provide a new way to alleviate the developmental neurotoxicity caused by propofol by correcting the dysregulation of calcium concentration.…”

Propofol Regulates the Proliferation and Migration of Lung Cancer Cells Through Atr Signaling Pathway

“…Evidence shows that propofol can regulate the occurrence and development of tumor cells. Retrospective study shows that, compared with inhalation anesthesia, total intravenous anesthesia by propofol can improve the overall survival of patients with various types of tumors [9]. Different from inhalation anesthetics and other intravenous anesthetics, propofol can inhibit the proliferation, migration, invasion and angiogenesis of various tumor cells by acting on different cell signal pathways, and restore or enhance the sensitivity of tumor cells to chemotherapeutic drugs [10].…”