Xiaopeng Tang1, Mingqian Fang1,2, Ruomei Cheng1,2, Zhiye Zhang1,3, Yuming Wang4, Chuanbin Shen1, Yajun Han1, Qiumin Lu1,3, Yingrong Du5, Yingying Liu6, Zhaohui Sun7, Liping Zhu8, James Mwangi1,2, Min Xue1, Chengbo Long1, Ren Lai1,9,10,11,12. 1. From the Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, China (X.T., M.F., R.C., Z.Z., C.S., Y.H., Q.L., J.M., M.X., C.L., R.L.). 2. Kunming College of Life Science, University of Chinese Academy of Sciences, Yunnan, China (M.F., R.C., J.M.). 3. Key Laboratory of Cardiovascular Disease of Yunnan Province, Kunming, Yunnan, China (Z.Z., Q.L.). 4. Department of Clinical Laboratory, the Second Affiliated Hospital of Kunming Medical University, Yunnan, China (Y.W.). 5. Department of Cardiology (Y.D.), the Third People's Hospital of Kunming, Yunnan, China. 6. Department of Clinical Laboratory (Y.L.), the Third People's Hospital of Kunming, Yunnan, China. 7. Department of Clinical Laboratory, Guangzhou General Hospital of Guangzhou Military Command, Guangdong, China (Z.S.). 8. Department of Clinical Laboratory, the First Affiliated Hospital of Kunming Medical University, Yunnan, China (L.Z.). 9. Institute for Drug Discovery and Development, Chinese Academy of Sciences, Shanghai, China (R.L.). 10. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases (R.L.), Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, China. 11. Sino-African Joint Research Center (R.L.), Kunming Institute of Zoology, Chinese Academy of Sciences, Yunnan, China. 12. Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China (R.L.).
Abstract
RATIONALE: Epidemiological 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 upregulate the level and iron-binding ability of Tf (transferrin), with our recent study showing that this upregulation can induce hypercoagulability by potentiating FXIIa/thrombin and blocking antithrombin-coagulation proteases interactions. OBJECTIVE: To investigate whether Tf mediates IS associated with ID or CC and the underlying mechanisms. METHODS AND RESULTS: Tf levels were assayed in the plasma of IS patients with a 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 and estrogen administration 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 and estrogen upregulated Tf through hypoxia and estrogen response elements located in the Tf gene enhancer and promoter regions, respectively. In addition, ID, administration of exogenous Tf or estrogen, 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 Tf 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 Tf-thrombin/FXIIa interactions.
RATIONALE: Epidemiological 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 upregulate the level and iron-binding ability of Tf (transferrin), with our recent study showing that this upregulation can induce hypercoagulability by potentiating FXIIa/thrombin and blocking antithrombin-coagulation proteases interactions. OBJECTIVE: To investigate whether Tf mediates IS associated with ID or CC and the underlying mechanisms. METHODS AND RESULTS: Tf levels were assayed in the plasma of IS patients with a history of ID anemia, ID anemia patients, venous thromboembolismpatients using CC, and ID mice, and in the cerebrospinal fluid of some IS patients. Effects of ID and estrogen administration 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 and estrogen upregulated Tf through hypoxia and estrogen response elements located in the Tf gene enhancer and promoter regions, respectively. In addition, ID, administration of exogenous Tf or estrogen, 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 Tf 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 Tf-thrombin/FXIIa interactions.
Authors: Yuan Sui; Chien-Tai Hong; Li-Nien Chien; Hung-Yi Liu; Hung-Yi Chiou; Yi-Chen Hsieh Journal: Int J Environ Res Public Health Date: 2020-10-13 Impact factor: 3.390