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Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.

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收录情况： ◇ SCIE

作者：
Cui Hongtu[1] * ; Chen Yanghui[2] * ; Li Ke[3] ; Zhan Rui[1] ; Zhao Mingming[1] ; Xu Yangkai[1] ; Lin Zhiyong[4] ; Fu Yi[5] ; He Qihua[6] ; Tang Paul C[7] ; Lei Ienglam[7] ; Zhang Jifeng[8] ; Li Chenze[9] ; Sun Yang[2] ; Zhang Xinhua[10] ; Horng Tiffany[11] ; Lu Hong S[12] ; Chen Y Eugene[7,8] ; Daugherty Alan[12] ; Wang Daowen[2] ; Zheng Lemin[1,3] ;
单位： [1]The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences ofMinistry of Education, Health Sciences Center, Peking University, Xueyuan Road NO.38, Haidian District, Beijing 100871, China [2]Division of Cardiology, Department of InternalMedicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue NO.1095, Qiaokou District, Wuhan 430000, China [3]BeijingTiantan Hospital, China National Clinical Research Center of Neurological Diseases, Advanced Innovation Center for Human Brain Protection, The Capital Medical University,Nan Si Huan Xi Lu NO.119, Fengtai District, Beijing 100050, China [4]Cardiology Division, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, USA [5]Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education,Xueyuan Road NO.38, Haidian District, Beijing 100191, China [6]Center of Medical and Health Analysis, Peking University, Xueyuan Road NO.38, Haidian District, Beijing 100191,China [7]Department of Cardiac Surgery, Frankel Cardiovascular Center, The University of Michigan, 500 S. State Street, Ann Arbor, MI 48109, USA [8]Department of InternalMedicine, The University of Michigan, 500 S. State Street, Ann Arbor, MI 48109, USA [9]Department of Cardiology, Zhongnan Hospital of Wuhan University, Donghu RoadNO.169, Wuchang District, Wuhan, China [10]Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education,Hebei Medical University, Zhongshan East Road NO.361, Shijiazhuang, Shijiazhuang 050017, China [11]ShanghaiTech University, Yueyang Road NO.319, Xuhui District, Shanghai201210, China [12]Department of Physiology, Saha Cardiovascular Research Center, University of Kentucky, South Limestone, Lexington, KY 40536-0298, USA
出处：
DOI： 10.1093/eurheartj/ehab605
ISSN：

关键词： Aortic aneurysm and dissection • Macrophage • Oxoglutarate dehydrogenase • Succinate

摘要：
Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance.We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD.Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

基金：
National Natural Science Foundation of China projects (No. 91639108, No. 81770272, No. 81970425, No. 91439203, No. 91839302, and No. 81901235), the National Key Research and Development Program of China (2020YFA0803700), and China Postdoctoral Science Foundation Grant (No. 2020T130004ZX).
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外文
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中科院(CAS)分区：
出版当年[2020]版：
大类 | 1 区 医学
小类 | 1 区 心脏和心血管系统
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 心脏和心血管系统
JCR分区：
出版当年[2019]版：
Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
最新[2023]版：
Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

影响因子： 最新[2023版] 最新五年平均 出版当年[2019版] 出版当年五年平均 出版前一年[2018版] 出版后一年[2020版]

第一作者：
第一作者单位： [1]The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences ofMinistry of Education, Health Sciences Center, Peking University, Xueyuan Road NO.38, Haidian District, Beijing 100871, China
共同第一作者：
通讯作者：
通讯机构： [1]The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences ofMinistry of Education, Health Sciences Center, Peking University, Xueyuan Road NO.38, Haidian District, Beijing 100871, China [3]BeijingTiantan Hospital, China National Clinical Research Center of Neurological Diseases, Advanced Innovation Center for Human Brain Protection, The Capital Medical University,Nan Si Huan Xi Lu NO.119, Fengtai District, Beijing 100050, China
推荐引用方式(GB/T 7714)：
Cui Hongtu,Chen Yanghui,Li Ke,et al.Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.[J].EUROPEAN HEART JOURNAL.2021,42(42):4373-4385.doi:10.1093/eurheartj/ehab605.
APA：
Cui Hongtu,Chen Yanghui,Li Ke,Zhan Rui,Zhao Mingming...&Zheng Lemin.(2021).Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection..EUROPEAN HEART JOURNAL,42,(42)
MLA：
Cui Hongtu,et al."Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.".EUROPEAN HEART JOURNAL 42..42(2021):4373-4385

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