Title: Iron-deficiency andestrogenareassociatedwithischemicstroke byup-regulatingtransferrin to Iiducehypercoagulability.
Author:Tang XP, FangMQ, ChengRM, ZhangZY, WangYM, ShenCB, HanYJ, LuQM, DuYG,LiuYY, SunZH, ZhuLP, Mwangi J, XueM, LongCB, Lai R.
Publication Name: Circ Res
Pub Year:2020
Doi: 10.1161/CIRCRESAHA.119.316453
IF:7.958
Abstract:
Rationale: Epidemiological studies have identified an associate betweeniron deficiency(ID) and the use of oral contraceptives (CC) andischemicstroke(IS). To date, however, the underlying mechanism remains poorly understood. Both ID and CC have been demonstrated to upregulate the level and iron-binding ability of Tf (transferrin),withour recent study showing that this upregulation can induce hypercoagulabilitybypotentiating FXIIa/thrombin and blocking antithrombin-coagulation proteases interactions. Objective: To investigate whether Tf mediates ISassociatedwithID or CC and the underlying mechanisms. Methods and Results: Tf levels were assayed in the plasma of IS patientswitha history of ID anemia, ID anemia patients, venous thromboembolism patients using CC, and ID mice, and in the cerebrospinal fluid of some IS patients. Effects of ID andestrogenadministration on Tf expression and coagulability and the underlying mechanisms were studied in vivo and in vitro. High levels of Tf and Tf-thrombin/FXIIa complexes were found in patients and ID mice. Both ID andestrogenupregulated Tf through hypoxia andestrogenresponse elements located in the Tf gene enhancer and promoter regions, respectively. In addition, ID, administration of exogenous Tf orestrogen, and Tf overexpression promoted platelet-based thrombin generation and hypercoagulability and thus aggravated IS. In contrast, anti-Tf antibodies, Tf knockdown, and peptide inhibitors of Tf-thrombin/FXIIa interaction exerted anti-IS effects in vivo. Conclusions: Our findings revealed that certain factors (ie, ID and CC) upregulating Tfarerisk 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 medicinebyinterferingwithTf-thrombin/FXIIa interactions.
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