PMID- 33462182 OWN - NLM STAT- MEDLINE DCOM- 20210929 LR - 20230919 IS - 2041-4889 (Electronic) VI - 12 IP - 1 DP - 2021 Jan 18 TI - Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway. PG - 88 LID - 10.1038/s41419-020-03357-1 [doi] LID - 88 AB - Inducing autophagy and inhibiting apoptosis may provide a therapeutic treatment for atherosclerosis (AS). For the treatment of progressive AS, arsenic trioxide (ATO) has been used to coat vascular stents. However, the effect of ATO on autophagy of macrophages is still unknown. Therefore, the aims of this study were to characterize the effects and the mechanism of actions of ATO on autophagy in macrophages. Our results showed that ATO-induced activation of autophagy was an earlier event than ATO-induced inhibition of the expression of apoptosis markers in macrophages and foam cells. Nuclear transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy and promoting lysosomal biogenesis. Here, we report that ATO triggered the nuclear translocation of TFEB, which in turn promoted autophagy and autophagosome-lysosome fusion. Both the latter events were prevented by TFEB knockdown. Moreover, ATO decreased the p-AKT and p-mTOR in the PI3K/AKT/mTOR signaling pathway, thus inducing autophagy. Correspondingly, treatment with the autophagy inhibitor 3-methyladenine (3-MA) abolished the autophagy-inducing effects of ATO. Meanwhile, PI3K inhibitor (LY294002) and mTOR inhibitor (rapamycin) cooperated with ATO to induce autophagy. Furthermore, reactive oxygen species (ROS) were generated in macrophages after treatment with ATO. The ROS scavenger N-acetyl-1-cysteine (NAC) abolished ATO-induced nuclear translocation of TFEB, as well as changes in key molecules of the AKT/mTOR signaling pathway and downstream autophagy. More importantly, ATO promoted autophagy in the aorta of ApoE(-/-) mice and reduced atherosclerotic lesions in early AS, which were reversed by 3-MA treatment. In summary, our data indicated that ATO promoted ROS induction, which resulted in nuclear translocation of TFEB and inhibition of the PI3K/AKT/mTOR pathway. These actions ultimately promoted macrophage autophagy and reduced atherosclerotic lesions at early stages. These findings may provide a new perspective for the clinical treatment of early-stage atherosclerosis and should be further studied. FAU - Fang, Shaohong AU - Fang S AD - Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. FAU - Wan, Xin AU - Wan X AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, China. FAU - Zou, Xiaoyi AU - Zou X AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, China. FAU - Sun, Song AU - Sun S AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, China. FAU - Hao, Xinran AU - Hao X AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, China. FAU - Liang, Chenchen AU - Liang C AD - Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. FAU - Zhang, Zhenming AU - Zhang Z AD - Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. FAU - Zhang, Fangni AU - Zhang F AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, China. FAU - Sun, Bo AU - Sun B AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. AD - Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, China. FAU - Li, Hulun AU - Li H AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. lihl_hrbmu@163.com. AD - Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, China. lihl_hrbmu@163.com. FAU - Yu, Bo AU - Yu B AD - Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. dryu_hmu@163.com. AD - The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, China. dryu_hmu@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210118 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Reactive Oxygen Species) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - S7V92P67HO (Arsenic Trioxide) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Arsenic Trioxide/*pharmacology MH - Atherosclerosis/drug therapy/pathology MH - Autophagy/drug effects MH - Cell Nucleus/metabolism MH - Humans MH - Macrophages/*drug effects/metabolism/pathology MH - Male MH - Mice MH - Proto-Oncogene Proteins c-akt/*metabolism MH - RAW 264.7 Cells MH - Reactive Oxygen Species/*metabolism MH - Signal Transduction/drug effects MH - THP-1 Cells MH - TOR Serine-Threonine Kinases/*metabolism MH - Transfection PMC - PMC7814005 COIS- The authors declare that they have no conflict of interest. EDAT- 2021/01/20 06:00 MHDA- 2021/09/30 06:00 PMCR- 2021/01/18 CRDT- 2021/01/19 05:50 PHST- 2020/05/20 00:00 [received] PHST- 2020/12/16 00:00 [accepted] PHST- 2020/12/14 00:00 [revised] PHST- 2021/01/19 05:50 [entrez] PHST- 2021/01/20 06:00 [pubmed] PHST- 2021/09/30 06:00 [medline] PHST- 2021/01/18 00:00 [pmc-release] AID - 10.1038/s41419-020-03357-1 [pii] AID - 3357 [pii] AID - 10.1038/s41419-020-03357-1 [doi] PST - epublish SO - Cell Death Dis. 2021 Jan 18;12(1):88. doi: 10.1038/s41419-020-03357-1.