Chloroquine Alleviates Atherosclerosis by Modulating Regulatory T Cells Through the ATM/AMPK/mTOR Signaling Pathway in ApoE −/− Mice

Author:

Liu Dan1,Zhang Yonggang2,Zhang Yiyi34,Huang Qiaorong5,Meng Wentong5,Gao Jinhang6,Mo Xianming5,Tian Haoming1,Li Sheyu1

Affiliation:

1. Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China

2. Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu, China

3. Department of Endocrinology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

4. Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, Sichuan, China

5. Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

6. Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China

Abstract

Abstract Background Clinical observation suggests the atheroprotective effect of chloroquine and its derivatives, while its mechanism remains unclear. This study aimed to observe the protective effect of chloroquine against atherosclerosis and explore the underlying mechanism. Methods Ataxia telangiectasia mutated (ATM) wild-type or haploinsufficient apolipoprotein-E-knockout (ATM+/+ApoE−/− or ATM+/−ApoE−/−) mice were treated with different dosages of chloroquine. Anti-CD25 antibody was used to deplete natural Tregs in ATM+/+ApoE−/− mice. The atherosclerotic burden in different groups of mice was comprehensively evaluated by H&E staining and Masson staining. The effect of chloroquine on the regulatory T cells (Tregs) was assessed in vivo and in vitro by flow cytometry and immunohistochemical staining. The expression of related proteins was detected by real-time polymerase chain reaction and western blotting. Results In ATM+/+ApoE−/− mice, chloroquine alleviated atherosclerotic lesions, stabilized the plaque, and increased Treg counts in the atherosclerotic lesions and spleens. However, in ATM haploinsufficient mice (ATM+/−ApoE−/−), chloroquine no longer prevented atherosclerosis or impacted Treg counts. Abolishing Treg cells using an anti-CD25 antibody in vivo abrogated the atheroprotective effect of chloroquine. In vitro, chloroquine promoted the differentiation of Tregs from naïve T cells, which was accompanied by enhanced ATM/AMP-activated protein kinase (AMPK) activity and reduced downstream mammalian target of rapamycin (mTOR) activity. Discussion These findings suggest that chloroquine ameliorates atherosclerosis and stabilizes plaque by modulating Tregs differentiation through the regulation of the ATM/AMPK/mTOR pathway.

Publisher

Georg Thieme Verlag KG

Subject

Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism,Internal Medicine

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2. Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis;International Journal of Molecular Sciences;2024-06-05

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