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Exp Clin Endocrinol Diabetes 2023; 131(12): 676-685
DOI: 10.1055/a-2201-8728
Article

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

Dan Liu
1   Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
,
Yonggang Zhang
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
,
Yiyi Zhang
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
,
Qiaorong Huang
5   Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
,
Wentong Meng
5   Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
,
Jinhang Gao
6   Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
,
Xianming Mo
5   Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
,
Haoming Tian
1   Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
,
Sheyu Li
1   Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
› Author Affiliations Fundings Sichuan Science and Technology Program — 2022YFH0114 National Natural Science Foundation of China — 81400811 1.3.5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University — 2020HXF011 the Space Medical Experiment Project of China Manned Space Program — HYZHXM01004
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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.

Key words

antimalarial drugs - cardiovascular diseases - Tregs - ataxia-telangiectasia mutated

Supplementary Material



Publication History

Received: 15 May 2023
Received: 18 August 2023

Accepted: 23 October 2023

Article published online:
06 December 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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