PMID- 34559203 OWN - NLM STAT- MEDLINE DCOM- 20220310 LR - 20220531 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 6 IP - 1 DP - 2022 Jan 11 TI - The binding of autotaxin to integrins mediates hyperhomocysteinemia-potentiated platelet activation and thrombosis in mice and humans. PG - 46-61 LID - 10.1182/bloodadvances.2021004572 [doi] AB - Hyperhomocysteinemia (HHcy) is associated with an exaggerated platelet thrombotic response at sites of vascular injury. In this study, human medical examination showed that elevated human plasma Hcy levels correlated positively with enhanced blood coagulation and platelet activity, suggesting that humans with HHcy are more prone to thrombus formation at the sites of vascular injury. Accordingly, we observed accelerated platelet activation, primary hemostasis, and thrombus formation in apolipoprotein E-deficient (ApoE-/-) mice with acute or chronic HHcy. Upon homocysteine (Hcy) administration in C57BL/6J mice, platelet aggregation, spreading and clot retraction were markedly induced. More important, Hcy increased the affinity of platelet integrin alphaIIbbeta3 with ligands and enhanced integrin outside-in signaling by promoting membrane phosphatidylserine exposure in vitro. Mechanistically, lipidomics analysis showed that lysophosphatidylcholines were the primary metabolites leading to clustering of HHcy-stimulated platelets. Cytosolic phospholipase A2 (cPLA2) activity and autotaxin (ATX, a secreted lysophospholipase D) secretion were upregulated by Hcy, leading to membrane phospholipid hydrolysis and PS exposure. Moreover, secreted ATX directly interacted with integrin beta3. Inhibitors of cPLA2 and ATX activity blocked integrin alphaIIbbeta3 outside-in signaling and thrombosis in HHcy ApoE-/- mice. In this study, we identified a novel mechanism by which HHcy promotes platelet membrane phospholipid catabolism and extracellular ATX secretion to activate integrin outside-in signaling, consequently exacerbating thrombosis and the results revealed an innovative approach to treating HHcy-related thrombotic diseases. CI - (c) 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. FAU - Han, Lulu AU - Han L AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University. AD - Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China. FAU - Miao, Yutong AU - Miao Y AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University. AD - Clinical Laboratory, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China. FAU - Zhao, Yang AU - Zhao Y AD - Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People's Republic of China. FAU - Zhang, Xingzhong AU - Zhang X AD - Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, People's Republic of China. FAU - Ma, Xiaolong AU - Ma X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University. AD - Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China. FAU - Du, Xing AU - Du X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University. AD - Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China. FAU - Kong, Wei AU - Kong W AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University. AD - Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China. FAU - Xu, Qingbo AU - Xu Q AD - Cardiovascular Division, British Heart Foundation (BHF) Center for Vascular Regeneration, King's College London, London, United Kingdom. FAU - Liu, Junling AU - Liu J AUID- ORCID: 0000-0002-2510-790X AD - Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. FAU - Dai, Kesheng AU - Dai K AD - Jiangsu Institute of Hematology, The First Affiliated Hospital and Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University; and. AD - Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou, People's Republic of China. FAU - Feng, Juan AU - Feng J AUID- ORCID: 0000-0003-0174-4784 AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University. AD - Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China. FAU - Wang, Xian AU - Wang X AD - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University. AD - Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, People's Republic of China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Platelet Glycoprotein GPIIb-IIIa Complex) RN - EC 3.1.4.- (Phosphoric Diester Hydrolases) RN - EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase) SB - IM MH - Animals MH - Humans MH - *Hyperhomocysteinemia/complications MH - Mice MH - Mice, Inbred C57BL MH - Phosphoric Diester Hydrolases MH - Platelet Activation MH - Platelet Glycoprotein GPIIb-IIIa Complex/metabolism MH - *Thrombosis/etiology/metabolism PMC - PMC8753216 EDAT- 2021/09/25 06:00 MHDA- 2022/03/11 06:00 PMCR- 2021/12/30 CRDT- 2021/09/24 12:18 PHST- 2021/02/22 00:00 [received] PHST- 2021/07/26 00:00 [accepted] PHST- 2021/09/25 06:00 [pubmed] PHST- 2022/03/11 06:00 [medline] PHST- 2021/09/24 12:18 [entrez] PHST- 2021/12/30 00:00 [pmc-release] AID - 477028 [pii] AID - 2021/ADV2021004572R3 [pii] AID - 10.1182/bloodadvances.2021004572 [doi] PST - ppublish SO - Blood Adv. 2022 Jan 11;6(1):46-61. doi: 10.1182/bloodadvances.2021004572.