Iron-Deficiency and Estrogen Are Associated With Ischemic Stroke by Up-Regulating Transferrin to Induce Hypercoagulability

Author:

Tang Xiaopeng1,Fang Mingqian12,Cheng Ruomei12,Zhang Zhiye13,Wang Yuming4,Shen Chuanbin1,Han Yajun1,Lu Qiumin13,Du Yingrong5,Liu Yingying6,Sun Zhaohui7,Zhu Liping8,Mwangi James12,Xue Min1,Long Chengbo1,Lai Ren19101112ORCID

Affiliation:

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.

Funder

National Natural Science Foundation of China

Chinese Academy of Sciences

Natural Science Foundation of Yunnan Province

Ministry of Science and Technology of the People's Republic of China

CAS | Youth Innovation Promotion Association

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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