Redox Biology (Oct 2024)
ALDH2 deficiency augments atherosclerosis through the USP14-cGAS-dependent polarization of proinflammatory macrophages
- Haiying Rui,
- Huaxiang Yu,
- Kai Chi,
- Ziqi Han,
- Wenyong Zhu,
- Jian Zhang,
- Haipeng Guo,
- Wenyi Zou,
- Fengxin Wang,
- Ping Xu,
- Dan Zou,
- Xiaoshuai Song,
- Lulu Liu,
- Xuting Wu,
- Wenxiao Wu,
- Dandan Qin,
- Yihai Cao,
- Feng Xu,
- Li Xue,
- Yuguo Chen
Affiliations
- Haiying Rui
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Huaxiang Yu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Kai Chi
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Ziqi Han
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Wenyong Zhu
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Qingdao, 266035, China
- Jian Zhang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Haipeng Guo
- Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Wenyi Zou
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Fengxin Wang
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Ping Xu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Dan Zou
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Xiaoshuai Song
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Lulu Liu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Xuting Wu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Wenxiao Wu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Dandan Qin
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China
- Yihai Cao
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, 17165, Sweden
- Feng Xu
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China; Corresponding author. Qilu Hospital of Shandong University, No.107, Wen Hua Xi Road, Jinan, Shandong 250012, China.
- Li Xue
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China; Corresponding author. Qilu Hospital of Shandong University, No.107, Wen Hua Xi Road, Jinan, Shandong 250012, China.
- Yuguo Chen
- Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Chest Pain Center, Qilu Hospital of Shandong University, Jinan, 250012, China; Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China; Shandong Key Laboratory, Magnetic Field-free Medicine & Functional Imaging (MF), Qilu Hospital of Shandong University, Jinan, 250012, China; NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Jinan, 250012, China; Corresponding author. Qilu Hospital of Shandong University, No.107, Wen Hua Xi Road, Jinan, Shandong 250012, China.
- Journal volume & issue
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Vol. 76
p. 103318
Abstract
The aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism commonly exists in the East Asian populations and is associated with high risks of cardiovascular disease (CVD). However, the cellular and molecular mechanisms that underlie the ALDH2 rs671 mutant-linked high CVD remain elusive. Here, we show that macrophages derived from human ALDH2 rs671 carriers and ALDH2 knockout mice exhibited an enhanced pro-inflammatory macrophage phenotype and an impaired anti-inflammatory macrophage phenotype. Transplanting bone marrow from ALDH2−/−ApoE−/− to ApoE−/− mice significantly increased atherosclerotic plaque growth and pro-inflammatory macrophage polarization in vivo. Mechanistically, ALDH2 inhibited activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in macrophages. Pharmacological inhibition of cGAS by RU.521 completely neutralized ALDH2-deficiency-induced macrophage polarization. In-depth mechanistic investigation showed that ALDH2 accelerated cGAS K48-linked polyubiquitination degradation at lysine 282 in macrophages by reducing the interaction between ubiquitin-specific protease 14 (USP14) and cGAS, mainly through its enzymatic role in mitigating 4-hydroxy-2-nonenal (4-HNE) accumulation. Consistently, USP14 knockdown in bone marrow cells alleviated proinflammatory responses in macrophages and protected against atherosclerosis. Our findings provide new mechanistic insights of ALDH2 deficiency-associated proinflammation and atherosclerosis and new therapeutic and preventive paradigms for treatment of atherosclerosis-associated CVD.
