Platelet HIF-2α promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release
| Autor: | Nazmy A. Latheef, JK Mishra, Geeta Kushwaha, Ram L. Mallick, Paresh P. Kulkarni, Susheel N. Chaurasia, Debabrata Dash |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Blood Platelets
Thrombogenicity Pulmonary disease Altitude Sickness Article Platelet Biology & its Disorders 03 medical and health sciences Extracellular Vesicles Mice Pulmonary Disease Chronic Obstructive 0302 clinical medicine Plasminogen Activator Inhibitor 1 medicine Basic Helix-Loop-Helix Transcription Factors Animals Humans Platelet Thrombus Cells Cultured Messenger RNA Chemistry Thrombosis Hematology Extracellular vesicle medicine.disease Prognosis Phenotype Cell biology Case-Control Studies Signal transduction 030215 immunology Follow-Up Studies Signal Transduction |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 0390-6078 |
| Popis: | Oxygen-compromised environments, such as high altitude, are associated with platelet hyperactivity. Platelets confined within the relatively impervious core of an aggregate/thrombus have restricted access to oxygen, yet they continue to perform energy-intensive procoagulant activities that sustain the thrombus. Studying platelet signaling under hypoxia is, therefore, critical to our understanding of the mechanistic basis of thrombus stability. We report here that hypoxia-inducible factor (HIF)-2α is translated from pre-existing mRNA and stabilized against proteolytic degradation in enucleate platelets exposed to hypoxia. Hypoxic stress, too, stimulates platelets to synthesize plasminogen-activator inhibitor-1 (PAI-1) and shed extracellular vesicles, both of which potentially contribute to the prothrombotic phenotype associated with hypoxia. Stabilization of HIF-α by administering hypoxia-mimetics to mice accelerates thrombus formation in mesenteric arterioles. In agreement, platelets from patients with chronic obstructive pulmonary disease and high altitude residents exhibiting thrombogenic attributes have abundant expression of HIF-2α and PAI- 1. Thus, targeting platelet hypoxia signaling could be an effective anti-thrombotic strategy. |
| Databáze: | OpenAIRE |
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