Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2β1.

Autor:	Huang K; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Li Z; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., He X; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Dai J; Guangzhou Customs District Technology Center, Guangzhou, Guangdong 510700, China., Huang B; College of Big Data and Internet, Shenzhen Technology University, Shenzhen, Guangdong 518118, China., Shi Y; Guangzhou Customs District Technology Center, Guangzhou, Guangdong 510700, China., Fan D; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Zhang Z; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Liu Y; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Li N; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Zhang Z; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Peng J; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Liu C; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Zeng R; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Cen Z; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Wang T; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Yang W; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Cen M; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China., Li J; College of Big Data and Internet, Shenzhen Technology University, Shenzhen, Guangdong 518118, China., Yuan S; Guangzhou Customs District Technology Center, Guangzhou, Guangdong 510700, China., Zhang L; Guangzhou Customs District Technology Center, Guangzhou, Guangdong 510700, China., Hu D; Guangzhou Customs District Technology Center, Guangzhou, Guangdong 510700, China., Huang S; Guangzhou Customs District Technology Center, Guangzhou, Guangdong 510700, China., Chen P; National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China., Lai P; Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China., Lin L; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Wen J; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Zhao Z; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Huang X; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Yuan L; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Zhou L; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Wu H; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Huang L; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China., Feng K; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Wang J; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Liao B; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Cai W; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Deng X; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Li Y; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Li J; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Hu Z; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Yang L; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Li J; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Zhuo Y; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Zhang F; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China., Lin L; Department of Respiratory Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China., Luo Y; Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Sun Yat-sen University, Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, Guangdong 510080, China., Zhang W; Wuhan Metware Biotechnology Co., Ltd., Wuhan, Hubei 430070, China., Ni Q; Wuhan Metware Biotechnology Co., Ltd., Wuhan, Hubei 430070, China., Hong X; Wuhan Metware Biotechnology Co., Ltd., Wuhan, Hubei 430070, China., Chang G; Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, China., Zhang Y; School of Public Health, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China., Guan D; Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Cai W; Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568, USA., Lu Y; National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China., Li F; Department of Obstetrics and Gynecology, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510620, China., Yan L; Guangdong Clinical Research Center for Metabolic Diseases (Diabetes), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China., Ren M; Guangdong Clinical Research Center for Metabolic Diseases (Diabetes), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China. Electronic address: renmeng80@139.com., Li L; Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510060, China. Electronic address: llheliza@126.com., Chen S; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China; Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, Guangdong 528200, China. Electronic address: chensf26@mail.sysu.edu.cn.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Mar 05; Vol. 36 (3), pp. 598-616.e9. Date of Electronic Publication: 2024 Feb 23.
DOI:	10.1016/j.cmet.2024.01.014
Abstrakt:	Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2β1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2β1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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