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Haematologica 2019 Volume 104(12):2482-2492
Platelet Biology & its Disorders
Platelet HIF-2a promotes thrombogenicity through PAI-1 synthesis and extracellular vesicle release
Susheel N. Chaurasia,1 Geeta Kushwaha,1 Paresh P. Kulkarni,1
Ram L. Mallick,2 Nazmy A. Latheef,3 Jai K. Mishra3 and Debabrata Dash1
1Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India; 2Department of Biochemistry, Birat Medical College & Teaching Hospital, Biratnagar, Nepal and 3Department of Tuberculosis & Respiratory Diseases, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
ABSTRACT
Oxygen-compromised environments, such as high altitude, are asso- ciated with platelet hyperactivity. Platelets confined within the rel- atively impervious core of an aggregate/thrombus have restricted access to oxygen, yet they continue to perform energy-intensive procoagu- lant 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)-2a 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-a by administering hypoxia-mimetics to mice accelerates thrombus forma- tion in mesenteric arterioles. In agreement, platelets from patients with chronic obstructive pulmonary disease and high altitude residents exhibit- ing thrombogenic attributes have abundant expression of HIF-2a and PAI- 1. Thus, targeting platelet hypoxia signaling could be an effective anti- thrombotic strategy.
Introduction
The essence of platelet function is response to stimuli. Once stimulated, platelets rapidly adhere to each other to form macroscopic aggregates. A thrombus is a meshwork of polymerized fibrin holding aggregated platelets and is essential for hemostasis. Intriguingly, platelets continue to perform energy-intensive tasks such as protein synthesis, retraction of the fibrin clot and shedding of extracellular vesi- cles (EV) while trapped within the tightly packed thrombus milieu, despite the fact that these cells remain significantly cut off from supplies of oxygen and nutrients. Understandably, access to oxygen drops progressively from the periphery of a mass of platelet aggregate (or thrombus) to its inner core, which would expose the platelets to a differential hypoxic stress. Notably, phosphatidylserine-positive platelets are known to be localized at the core of a thrombus.1 Platelet response to hypoxia could influence the stability of platelet aggregates as well as sustenance of the thrombus. Thus, targeting hypoxia signaling could be an effective therapeutic strategy to destabilize pathological thrombi. As little is known about signaling dynamics in platelets exposed to hypoxic stress, in this study we explored the nature of hypoxia signaling and its regulation in human platelets.
Hypoxia-inducible factor (HIF) consists of an oxygen sensing a subunit and a constitutively expressed β subunit and has a central role in oxygen homeostasis.2 The a subunit exists in three oxygen-sensitive isoforms (HIF-1a, -2a and -3a):3 HIF- 1a is ubiquitously expressed while the presence of HIF-2a and -3a is cell-specific.4,5 The stability of HIF-a is determined by the hydroxylation status of specific proline residues catalyzed by prolyl hydroxylases (PHD1, 2 and 3), which are molecular oxygen-, 2-oxoglutarate-, and iron-dependent enzymes.2,6 Under normoxia,
Correspondence:
DEBABRATA DASH
ddash.biochem@gmail.com
Received: January 24, 2019. Accepted: April 17, 2019. Pre-published: April 19, 2019.
doi:10.3324/haematol.2019.217463
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/12/2482
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