机构:[1]Key Laboratory of Animal Models and Human Disease Mechanismsof Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, China[2]Department of Clinical Laboratory, the Second Affiliated Hospital of Kunming Medical University, Yunnan, China[3]Department of Cardiology , the ThirdPeople’s Hospital of Kunming, Yunnan, China[4]Department of Clinical Laboratory , the ThirdPeople’s Hospital of Kunming, Yunnan, China[5]Kunming College of Life Science,University of Chinese Academy of Sciences, Yunnan, China[6]Department of Clinical Laboratory, Guangzhou General Hospital of GuangzhouMilitary Command, Guangdong, China[7]Department of Clinical Laboratory,the First Affiliated Hospital of Kunming Medical University, Yunnan, China昆明医科大学附属第一医院[8]Institute for Drug Discovery and Development, Chinese Academy of Sciences,Shanghai, China[9]KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases , Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, China[10]Sino-African Joint ResearchCenter , Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, China[11]Center for Biosafety Mega-Science, Chinese Academy of Sciences,Wuhan, Hubei, China[12]Key Laboratory of Cardiovascular Disease ofYunnan Province, Kunming, Yunnan, China .
Rationale: Epidemiologic studies have identified an associate between iron deficiency (ID) and the use of oral contraceptives (CC) and ischemic stroke (IS). To date, however, the underlying mechanism remains poorly understood. Both ID and CC have been demonstrated to up-regulate the level and iron-binding ability of transferrin, with our recent study showing that this up-regulation can induce hypercoagulability by potentiating FXIIa/thrombin and blocking antithrombin-coagulation proteases interactions. Objective: To investigate whether transferrin mediates IS associated with ID or CC and the underlying mechanisms. Methods and Results:Transferrin levels were assayed in the plasma of IS patients with a history of iron-deficiency anemia (IDA), IDA patients, venous thromboembolism patients using CC, and ID mice, and in the cerebrospinal fluid of some IS patients. Effects of ID and estrogen administration on transferrin expression and coagulability and the underlying mechanisms were studied in vivo and in vitro. High levels of transferrin and transferrin-thrombin/FXIIa complexes were found in patients and ID mice. Both ID and estrogen up-regulated transferrin through hypoxia and estrogen response elements located in the transferrin gene enhancer and promoter regions, respectively. In addition, ID, administration of exogenous transferrin or estrogen, and transferrin overexpression promoted platelet-based thrombin generation and hypercoagulability, and thus aggravated IS. In contrast, anti-transferrin antibodies, transferrin knockdown, and peptide inhibitors of transferrin-thrombin/FXIIa interaction exerted anti-IS effects in vivo. Conclusions: Our findings revealed that certain factors (i.e., ID and CC) up-regulating transferrin are risk factors of thromboembolic diseases decipher a previously unrecognized mechanistic association among ID, CC and IS and provide a novel strategy for the development of anti-IS medicine by interfering with transferrin-thrombin/FXIIa interactions.
基金:
National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [31930015, 21761142002, 31630075, 81770464]; Chinese Academy of SciencesChinese Academy of Sciences [XDB31000000, KFJ-STS-SCYD-304, QYZDJ-SSW-SMC012, ZSTH-034, SAJC201606, XDA12040221]; Yunnan Province [2019ZF003, 2018ZF001]; Ministry of Science and Technology of ChinaMinistry of Science and Technology, China [2018YFA0801403]; Chinese Academy of Sciences (Youth Innovation Promotion Association) [2017432]
第一作者机构:[1]Key Laboratory of Animal Models and Human Disease Mechanismsof Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, China
共同第一作者:
通讯作者:
通讯机构:[1]Key Laboratory of Animal Models and Human Disease Mechanismsof Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, China[8]Institute for Drug Discovery and Development, Chinese Academy of Sciences,Shanghai, China[9]KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases , Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, China[10]Sino-African Joint ResearchCenter , Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, China[11]Center for Biosafety Mega-Science, Chinese Academy of Sciences,Wuhan, Hubei, China[*1]Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China.
推荐引用方式(GB/T 7714):
Tang Xiaopeng,Fang Mingqian,Cheng Ruomei,et al.Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability.[J].CIRCULATION RESEARCH.2020,127(5):651-663.doi:10.1161/CIRCRESAHA.119.316453.
APA:
Tang Xiaopeng,Fang Mingqian,Cheng Ruomei,Zhang Zhiye,Wang Yuming...&Lai Ren.(2020).Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability..CIRCULATION RESEARCH,127,(5)
MLA:
Tang Xiaopeng,et al."Iron-Deficiency and Estrogen Are Associated with Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability.".CIRCULATION RESEARCH 127..5(2020):651-663