Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation

Xiaobo B Han,Dou Dou,Yueqing Q Jiang,You Wang,Jing Li,Zhongni N Liu,Jiayuan Y Kou,Hao Wang,Yinghong H Zheng,Ye Tian,Xuesong S Li,Hong Li,Hongxia X Li,Liming M Yang

doi:10.1038/cddis.2017.242

Abstract

Macrophage-derived foam cells are a major component of atherosclerotic plaques and have an important role in the progression of atherosclerotic plaques, thus posing a great threat to human health. Photodynamic therapy (PDT) has emerged as a therapeutic strategy for atherosclerosis. Here, we investigated the effect of PDT mediated by upconversion fluorescent nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) on the cholesterol efflux of THP-1 macrophage-derived foam cells and explored the possible mechanism of this effect. First, we found that PDT notably enhanced the cholesterol efflux and the induction of autophagy in both THP-1 and peritoneal macrophage-derived foam cells. The autophagy inhibitor 3-methyladenine and an ATG5 siRNA significantly attenuated PDT-induced autophagy, which subsequently suppressed the ABCA1-mediated cholesterol efflux. Furthermore, the reactive oxygen species (ROS) produced by PDT were responsible for the induction of autophagy, which could be blocked by the ROS inhibitor N-acetyl cysteine (NAC). NAC also reversed the PDT-induced suppression of p-mTOR and p-Akt. Therefore, our findings demonstrate that PDT promotes cholesterol efflux by inducing autophagy, and the autophagy was mediated in part through the ROS/PI3K/Akt/mTOR signaling pathway in THP-1 and peritoneal macrophage-derived foam cells.

Highlights

Atherosclerosis is a chronic inflammatory cardiovascular disease that is the leading cause of death in industrialized societies and worldwide.[1]
Based on the vital roles of autophagy in cholesterol homeostasis, we explored the effect of upconversion nanoparticles (UCNPs)-Ce6mediated Photodynamic therapy (PDT) on cholesterol efflux by activating the autophagic process via reactive oxygen species (ROS) generation
We found that ABCA1 expression increased following PDT, whereas ABCG1 expression showed no obvious changes (Figure 4e), suggesting that the cholesterol efflux was mediated by ABCA1

Summary

Introduction

Atherosclerosis is a chronic inflammatory cardiovascular disease that is the leading cause of death in industrialized societies and worldwide.[1]. As major products of PDT, reactive oxygen species (ROS) generation was able to induce mitochondrial dysfunction, leading to cell death.[13,14] emerging evidence has confirmed that ROS are early inducers of autophagy.[15] Autophagy is an evolutionarily conserved process that responds to cellular stress conditions to maintain a healthy cellular status by degrading and recycling cytoplasmic contents via the lysosomal route.[16,17] Numerous reports have shown that autophagy participates in the regulation of lipid metabolism and cholesterol homeostasis, with a special emphasis on macrophage-derived foam cells.[18,19]. The aim of this study was to investigate whether UCNPs-Ce6-mediated PDT contributed to cholesterol homeostasis via the activation of autophagy

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Conclusion