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Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway.

ABSTRACT: 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.

SUBMITTER: Fang S

PROVIDER: S-EPMC7814005 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway.

Fang Shaohong S Wan Xin X Zou Xiaoyi X Sun Song S Hao Xinran X Liang Chenchen C Zhang Zhenming Z Zhang Fangni F Sun Bo B Li Hulun H Yu Bo B

Cell death & disease 20210118 1

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- ...[more]

PMID: 33462182

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Project description:Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY-SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway. Besides, TFEB nuclear translocation in macrophage was triggered by HY-SDT to promote autophagy activation and lysosome regeneration which enhanced lipid degradation in response to atherogenic lipid stressors. Moreover, following HY-SDT, the ABCA1 expression level was increased to promote lipid efflux in macrophage, and the expression levels of CD36 and SR-A were decreased to inhibit lipid uptake, both of which were prevented by TFEB knockdown. These results indicated that TFEB nuclear translocation activated by HY-SDT was not only the key regulator of autophagy activation and lysosome regeneration in macrophage to promote lipolysis, but also had a crucial role in reverse cholesterol transporters to decrease lipid uptake and increase lipid efflux. Reactive oxygen species (ROS) were adequately generated in macrophage by HY-SDT. Further, ROS scavenger N-acetyl-l-cysteine abolished HY-SDT-induced TFEB nuclear translocation and autophagy activation, implying that ROS were the primary upstream factors responsible for these effects during HY-SDT. In summary, our data indicate that HY-SDT decreases lipid content in macrophage by promoting ROS-dependent nuclear translocation of TFEB to influence consequent autophagy activation and cholesterol transporters. Thus, HY-SDT may be beneficial for atherosclerosis via TFEB regulation to ameliorate lipid overload in atherosclerotic plaques.

Project description:α-Solanine is a glycoalkaloid found in species of the nightshade family including potato. It was primarily reported to have toxic effects in humans. However, there is a growing body of literature demonstrating in vitro and in vivo anticancer activity of α-solanine. Most of these studies have shown activation of apoptosis as the underlying mechanism in antitumor activity of α-solanine. In this study, we report α-solanine as a potential inducer of autophagy, which may act synergistically or in parallel with apoptosis to exert its cytotoxic effect. Induction of autophagy was demonstrated by several assays including electron microscopy, immunoblotting of autophagy markers and immunofluorescence for LC3 (microtubule-associated protein 1 (MAP1) light chain-3) puncta. α-Solanine-induced autophagic flux was demonstrated by additionally enhanced--turnover of LC3-II and--accumulation of LC3-specific puncta after co-incubation of cells with either of the autophagolysosome inhibitors--chloroquine and--bafilomycin A1. We also demonstrated α-solanine-induced oxidative damage in regulating autophagy where pre-incubation of cells with reactive oxygen species (ROS) scavenger resulted in suppression of CM-H2DCFDA (5 (and 6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate acetyl ester) fluorescence as well as decrease in LC3-II turnover. α-Solanine treatment caused an increase in the expression of endoplasmic reticulum (ER) stress proteins (BiP, activating transcription factor 6 (ATF6), X-box-binding protein 1, PERK, inositol-requiring transmembrane kinase/endonuclease 1, ATF4 and CCAAT-enhancer-binding protein (C/EBP)-homologous protein) suggesting activation of unfolded protein response pathway. Moreover, we found downregulation of phosphorylated Akt (Thr308 and Ser473), mammalian target of rapamycin (mTOR; Ser2448 and Ser2481) and 4E-BP1 (Thr37/46) by α-solanine implying suppression of the Akt/mTOR pathway. Collectively, our results signify that α-solanine induces autophagy to exert anti-proliferative activity by triggering ER stress and inhibiting Akt/mTOR signaling pathway.

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Dataset Information

Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway.

Publications

Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway.

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