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

doi:10.1093/eurheartj/ehab605

	Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection
	Cui, Hongtu 1,2; Chen, Yanghui 3; Li, Ke 4; Zhan, Rui 1,2; Zhao, Mingming 1,2; Xu, Yangkai 1,2; Lin, Zhiyong 5; Fu, Yi 6; He, Qihua 7; Tang, Paul C.8; Lei, Ienglam 8; Zhang, Jifeng 9; Li, Chenze 10; Sun, Yang 3; Zhang, Xinhua 11; Horng, Tiffany12 ; Lu, Hong S.13; Chen, Y. Eugene 8,9; Daugherty, Alan 13; Wang, Daowen 3; Zheng, Lemin 1,2,4
	2021-11-07
发表期刊	EUROPEAN HEART JOURNAL (IF:37.6[JCR-2023],32.6[5-Year])
ISSN	0195-668X
EISSN	1522-9645
卷号	42 期号:42
发表状态	已发表
DOI	10.1093/eurheartj/ehab605
摘要	["Aims 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.","Methods and results 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 p38 alpha(MKO)Apoe(-/-) 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 p38 alpha decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38 alpha in macrophages reduced angiotensin II-induced AAD.","Conclusion 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 p38 alpha-CREB-OGDH axis in macrophages."]
关键词	Aortic aneurysm and dissection Macrophage Oxoglutarate dehydrogenase Succinate
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[91639108,81770272,81970425,91439203,91839302,81901235] ; National Key Research and Development Program of China[2020YFA0803700] ; China Postdoctoral Science Foundation[2020T130004ZX]
WOS研究方向	Cardiovascular System & Cardiology
WOS类目	Cardiac & Cardiovascular Systems
WOS记录号	WOS:000720765900016
出版者	OXFORD UNIV PRESS
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/135621
专题	生命科学与技术学院_PI研究组_洪诗雅组
通讯作者	Wang, Daowen; Zheng, Lemin
作者单位	1.Peking Univ, Inst Cardiovasc Sci, Xueyuan Rd 38, Beijing 100871, Peoples R China 2.Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Inst Syst Biomed,Minist Educ,Key Lab Mol Cardiova, Xueyuan Rd 38, Beijing 100871, Peoples R China 3.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med,Div Cardiol, Jiefang Ave 1095, Wuhan 430000, Peoples R China 4.Capital Med Univ, Beijing Tiantan Hosp, China Natl Clin Res Ctr Neurol Dis, Adv Innovat Ctr Human Brain Protect, Nan Si Huan Xi Lu 119, Beijing 100050, Peoples R China 5.Emory Univ, Sch Med, Div Cardiol, 100 Woodruff Circle, Atlanta, GA 30322 USA 6.Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Minist Educ,Key Lab Mol Cardiovasc Sci, Xueyuan Rd 38, Beijing 100191, Peoples R China 7.Peking Univ, Ctr Med & Hlth Anal, Xueyuan Rd 38, Beijing 100191, Peoples R China 8.Univ Michigan, Frankel Cardiovasc Ctr, Dept Cardiac Surg, 500 S State St, Ann Arbor, MI 48109 USA 9.Univ Michigan, Dept Internal Med, 500 S State St, Ann Arbor, MI 48109 USA 10.Wuhan Univ, Zhongnan Hosp, Dept Cardiol, Donghu Rd 169, Wuhan, Peoples R China 11.Hebei Med Univ, Dept Biochem & Mol Biol, Minist Educ, Key Lab Neural & Vasc Biol, Zhongshan East Rd 361, Shijiazhuang 050017, Hebei, Peoples R China 12.ShanghaiTech Univ, Yueyang Rd 319, Shanghai 201210, Peoples R China 13.Univ Kentucky, Saha Cardiovasc Res Ctr, Dept Physiol, South Limestone, Lexington, KY 40536 USA
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).
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).