Platelet HIF-2α promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release
Identifieur interne : 000534 ( Main/Exploration ); précédent : 000533; suivant : 000535Platelet HIF-2α promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release
Auteurs : Susheel N. Chaurasia [Inde] ; Geeta Kushwaha [Inde] ; Paresh P. Kulkarni [Inde] ; Ram L. Mallick [Népal] ; Nazmy A. Latheef [Inde] ; Jai K. Mishra [Inde] ; Debabrata Dash [Inde]Source :
- Haematologica [ 0390-6078 ] ; 2019.
Abstract
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.
Url:
DOI: 10.3324/haematol.2019.217463
PubMed: 31004026
PubMed Central: 6959171
Affiliations:
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Chaurasia</name><affiliation wicri:level="1"><nlm:aff id="af1-1042482">Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi</wicri:regionArea><wicri:noRegion>Varanasi</wicri:noRegion></affiliation></author><author><name sortKey="Kushwaha, Geeta" sort="Kushwaha, Geeta" uniqKey="Kushwaha G" first="Geeta" last="Kushwaha">Geeta Kushwaha</name><affiliation wicri:level="1"><nlm:aff id="af1-1042482">Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi</wicri:regionArea><wicri:noRegion>Varanasi</wicri:noRegion></affiliation></author><author><name sortKey="Kulkarni, Paresh P" sort="Kulkarni, Paresh P" uniqKey="Kulkarni P" first="Paresh P." last="Kulkarni">Paresh P. Kulkarni</name><affiliation wicri:level="1"><nlm:aff id="af1-1042482">Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi</wicri:regionArea><wicri:noRegion>Varanasi</wicri:noRegion></affiliation></author><author><name sortKey="Mallick, Ram L" sort="Mallick, Ram L" uniqKey="Mallick R" first="Ram L." last="Mallick">Ram L. Mallick</name><affiliation wicri:level="1"><nlm:aff id="af2-1042482">Department of Biochemistry, Birat Medical College & Teaching Hospital, Biratnagar, Nepal</nlm:aff><country xml:lang="fr">Népal</country><wicri:regionArea>Department of Biochemistry, Birat Medical College & Teaching Hospital, Biratnagar</wicri:regionArea><wicri:noRegion>Biratnagar</wicri:noRegion></affiliation></author><author><name sortKey="Latheef, Nazmy A" sort="Latheef, Nazmy A" uniqKey="Latheef N" first="Nazmy A." last="Latheef">Nazmy A. Latheef</name><affiliation wicri:level="1"><nlm:aff id="af3-1042482">Department of Tuberculosis & Respiratory Diseases, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Tuberculosis & Respiratory Diseases, Institute of Medical Sciences, Banaras Hindu University, Varanasi</wicri:regionArea><wicri:noRegion>Varanasi</wicri:noRegion></affiliation></author><author><name sortKey="Mishra, Jai K" sort="Mishra, Jai K" uniqKey="Mishra J" first="Jai K." last="Mishra">Jai K. Mishra</name><affiliation wicri:level="1"><nlm:aff id="af3-1042482">Department of Tuberculosis & Respiratory Diseases, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Tuberculosis & Respiratory Diseases, Institute of Medical Sciences, Banaras Hindu University, Varanasi</wicri:regionArea><wicri:noRegion>Varanasi</wicri:noRegion></affiliation></author><author><name sortKey="Dash, Debabrata" sort="Dash, Debabrata" uniqKey="Dash D" first="Debabrata" last="Dash">Debabrata Dash</name><affiliation wicri:level="1"><nlm:aff id="af1-1042482">Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi</wicri:regionArea><wicri:noRegion>Varanasi</wicri:noRegion></affiliation></author></analytic><series><title level="j">Haematologica</title><idno type="ISSN">0390-6078</idno><idno type="eISSN">1592-8721</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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. 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Vernooy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maclay, Jd" uniqKey="Maclay J">JD Maclay</name></author><author><name sortKey="Mcallister, Da" uniqKey="Mcallister D">DA McAllister</name></author><author><name sortKey="Johnston, S" uniqKey="Johnston S">S Johnston</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcredmond, Jp" uniqKey="Mcredmond J">JP McRedmond</name></author><author><name sortKey="Park, Sd" uniqKey="Park S">SD Park</name></author><author><name sortKey="Reilly, Df" uniqKey="Reilly D">DF Reilly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hansell, Al" uniqKey="Hansell A">AL Hansell</name></author><author><name sortKey="Walk, Ja" uniqKey="Walk J">JA Walk</name></author><author><name sortKey="Soriano, Jb" uniqKey="Soriano J">JB Soriano</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Inde</li><li>Népal</li></country></list><tree><country name="Inde"><noRegion><name sortKey="Chaurasia, Susheel N" sort="Chaurasia, Susheel N" uniqKey="Chaurasia S" first="Susheel N." last="Chaurasia">Susheel N. Chaurasia</name></noRegion><name sortKey="Dash, Debabrata" sort="Dash, Debabrata" uniqKey="Dash D" first="Debabrata" last="Dash">Debabrata Dash</name><name sortKey="Kulkarni, Paresh P" sort="Kulkarni, Paresh P" uniqKey="Kulkarni P" first="Paresh P." last="Kulkarni">Paresh P. Kulkarni</name><name sortKey="Kushwaha, Geeta" sort="Kushwaha, Geeta" uniqKey="Kushwaha G" first="Geeta" last="Kushwaha">Geeta Kushwaha</name><name sortKey="Latheef, Nazmy A" sort="Latheef, Nazmy A" uniqKey="Latheef N" first="Nazmy A." last="Latheef">Nazmy A. Latheef</name><name sortKey="Mishra, Jai K" sort="Mishra, Jai K" uniqKey="Mishra J" first="Jai K." last="Mishra">Jai K. Mishra</name></country><country name="Népal"><noRegion><name sortKey="Mallick, Ram L" sort="Mallick, Ram L" uniqKey="Mallick R" first="Ram L." last="Mallick">Ram L. Mallick</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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