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Effect of autophagy on ferroptosis in foam cells via Nrf2

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Abstract

The progression of atherosclerotic plaque is accelerated by death of foam cells during the development of the plaque. There are several forms of foam cell death, such as autophagy and ferroptosis forms of cell death together are commonly predominant. Therefore, it is particularly important to study the crosstalk between various forms of cell death in atheroscler and ferroptosis. Although there is a dominant form of cell death that plays a role in the disease, motic plaques. Nuclear factor NF-E2-related factor (Nrf2) has been considered as a major regulator of antioxidant in previous studies, but recent studies have revealed that insufficient cellular autophagy can turn off Nrf2-mediated antioxidant defense while initiating Nrf2-manipulated iron deposition and lipid peroxidation, leading to the development of iron ferroptosis. The present experiment aimed to explain the regulatory mechanism between autophagy and ferroptosis through Nrf2. In this experiment, differentiated human THP-1 macrophages were used, which were treated with ox-LDL into foam cells with the addition of the autophagy inhibitor chloroquine (CQ), the inhibitor of Nrf2 (ML385), the promoter of Nrf2 (t-BHQ), and the inhibitor of ferroptosis (Liproxstatin-1), and the expression levels of autophagy-related proteins p62 and LC3, as well as Nrf2 and ferroptosis-related proteins xCT and GPX4 by WB, foam cell survival by CCK8, and intracellular reactive oxygen levels by Flow cytometry analysis and fluorescence microscopy. The effect of autophagy through Nrf2 on ferroptosis in foam cells was determined. The results revealed that insufficient autophagy in CQ-induced foam cells could lead to foam cell death in atherosclerotic plaques, and the cause of cell death was that insufficient autophagy in foam cells turned off the positive effect of Nfr2 antioxidant, initiated the negative effect of Nrf2 to promote intracellular reactive oxygen species production, and this negative effect promoted ferroptosis in foam cells.

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Abbreviations

AS:

Atherosclerosis

AP:

Atherosclerotic plaque

ATG5:

Autophagy-related gene5

ATG7:

Autophagy-related gene7

CQ:

Chloroquine

CCK8:

Cell Counting Kit-8

DFC:

Iron chelator desferricoprogen

FCM:

Flow cytometry analysis

FBS:

Fetal bovine serum

Hmox1:

Heme oxygenase-1

GPX4:

Glutathione Peroxidase 4

LC3:

Microtubule-associated protein 1 light chain 3

Lipro-1:

Liproxstatin-1

Nrf2:

Nuclear factor erytheroid-derived-2-like 2

ox-LDL:

Oxidized-low-density lipoprotein

p62/SQSTM1:

Sequestosome 1

PMA:

Phorbol-12-myristate-13-ace-tate

ROS:

Reactive oxygen species

tBHQ:

Tert-butylhydroquinone

Xct:

Cystine-glutamic acid reverse transporter light chain protein

WB:

Western blot

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Funding

This study was supported by the grants from the National Natural Science Foundation of China (No. 81672084).

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Authors and Affiliations

  1. Department of Laboratory Diagnostics, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, NanGang, Harbin, Heilongjiang, 150001, People’s Republic of China

    Qi Peng, Huihui Liu, Zhisheng Luo, Haiyan Zhao, Xinming Wang & Xiuru Guan

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  1. Qi Peng
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  2. Huihui Liu
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  3. Zhisheng Luo
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  4. Haiyan Zhao
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  5. Xinming Wang
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Contributions

First author: do experiments, write articles, participate in part of the experimental design. Second, third, fourth and fifth Author: assist in completing the experiment. Corresponding author: participate in article revision, experimental design and supervision, financial support. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Xiuru Guan.

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Peng, Q., Liu, H., Luo, Z. et al. Effect of autophagy on ferroptosis in foam cells via Nrf2. Mol Cell Biochem 477, 1597–1606 (2022). https://doi.org/10.1007/s11010-021-04347-3

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