Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages
Shuai Zhao,
Lei Zhou,
Qin Wang,
Jia-Hao Cao,
Yan Chen,
Wei Wang,
Bo-Da Zhu,
Zhi-Hong Wei,
Rong Li,
Cong-Ye Li,
Geng-Yao Zhou,
Zhi-Jun Tan,
He-Ping Zhou,
Cheng-Xiang Li,
Hao-Kao Gao,
Xu-Jun Qin,
Kun Lian
Affiliations
Shuai Zhao
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Lei Zhou
Department of Clinical Laboratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Qin Wang
Department of Pharmacogenomics, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Jia-Hao Cao
School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712046, China
Yan Chen
Department of Cardiology, No.971 Hospital of the PLA Navy, Qingdao, Shandong, 266071, China
Wei Wang
Department of Clinical Laboratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Bo-Da Zhu
Primary Flight Training Base, Air Force Aviation University, Harbin, Heilongjiang, 150100, China
Zhi-Hong Wei
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Rong Li
Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Cong-Ye Li
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Geng-Yao Zhou
Department of Nutrition and Food Hygiene, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Zhi-Jun Tan
Department of Health Statistics, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
He-Ping Zhou
Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
Cheng-Xiang Li
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
Hao-Kao Gao
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Corresponding author. Department of Cardiology, Xijing Hospital, the Forth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China.
Xu-Jun Qin
Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China; Corresponding author. Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shaanxi, 710072, China.
Kun Lian
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Corresponding author. Department of Cardiology, Xijing Hospital, the Forth Military Medical University, 127 West Changle Road, Xi'an, Shaanxi, 710032, China.
As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE−/− mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.
