Journal article
Estradiol-responsive miR-365a-3p interacts with tissue factor 3′UTR to modulate tissue factor-initiated thrombin generation
Thrombosis and Haemostasis, Vol.121(11), pp.1483-1496
2021
Abstract
Background: High estradiol (E2) levels are linked to an increased risk of venous thromboembolism; however, the underlying molecular mechanism(s) remain poorly understood. We previously identified an E2-responsive microRNA (miR), miR-494–3p, that downregulates protein S expression, and posited additional coagulation factors, such as tissue factor, may be regulated in a similar manner via miRs.
Objectives: To evaluate the coagulation capacity of cohorts with high physiological E2, and to further characterize novel E2-responsive miR and miR regulation on tissue factor in E2-related hypercoagulability.
Methods: Ceveron Alpha thrombin generation assay (TGA) was used to assess plasma coagulation profile of three cohorts. The effect of physiological levels of E2, 10 nM, on miR expression in HuH-7 cells was compared using NanoString nCounter and validated with independent assays. The effect of tissue factor-interacting miR was confirmed by dual-luciferase reporter assays, immunoblotting, flow cytometry, biochemistry assays, and TGA.
Results: Plasma samples from pregnant women and women on the contraceptive pill were confirmed to be hypercoagulable (compared with sex-matched controls). At equivalent and high physiological levels of E2, miR-365a-3p displayed concordant E2 downregulation in two independent miR quantification platforms, and tissue factor protein was upregulated by E2 treatment. Direct interaction between miR-365a-3p and F3-3′UTR was confirmed and overexpression of miR-365a-3p led to a decrease of (1) tissue factor mRNA transcripts, (2) protein levels, (3) activity, and (4) tissue factor-initiated thrombin generation.
Conclusion: miR-365a-3p is a novel tissue factor regulator. High E2 concentrations induce a hypercoagulable state via a miR network specific for coagulation factors.
Details
- Title
- Estradiol-responsive miR-365a-3p interacts with tissue factor 3′UTR to modulate tissue factor-initiated thrombin generation
- Authors/Creators
- J. Tian (Author/Creator) - Murdoch UniversityM.J. Adams (Author/Creator) - Murdoch UniversityJ.W.T. Tay (Author/Creator)I. James (Author/Creator) - Murdoch UniversityS. Powell (Author/Creator) - Murdoch UniversityQ.W. Hughes (Author/Creator) - Pathwest Laboratory MedicineG. Gilmore (Author/Creator) - Gulf Coast Regional Blood CenterR.I. Baker (Author/Creator) - Murdoch UniversityJ.Y-H. Tiao (Author/Creator)
- Publication Details
- Thrombosis and Haemostasis, Vol.121(11), pp.1483-1496
- Publisher
- Schattauer
- Identifiers
- 991005539996007891
- Copyright
- © 2021 Thieme
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics; Health Futures Institute; Institute for Immunology and Infectious Diseases; Western Australian Centre for Thrombosis and Haemostasis
- Language
- English
- Resource Type
- Journal article
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- Citation topics
- 1 Clinical & Life Sciences
- 1.196 Micro & Long Noncoding RNA
- 1.196.68 MicroRNA in Cancer
- Web Of Science research areas
- Hematology
- Peripheral Vascular Disease
- ESI research areas
- Clinical Medicine