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Haematologica 2019 Volume 104(4):806-818
Platelet Biology & its Disorders
Aerobic glycolysis fuels platelet activation: small-molecule modulators of platelet metabolism as anti-thrombotic agents
Paresh P. Kulkarni,1† Arundhati Tiwari,1† Nitesh Singh,1 Deepa Gautam,1 Vijay K. Sonkar,1 Vikas Agarwal2 and Debabrata Dash1
1Department of Biochemistry, Institute of Medical Sciences and 2Department of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
†PPK and AT contributed equally to this work.
ABSTRACT
Platelets are critical to arterial thrombosis, which underlies myocardial infarction and stroke. Activated platelets, regardless of the nature of their stimulus, initiate energy-intensive processes that sustain throm- bus, while adapting to potential adversities of hypoxia and nutrient depri- vation within the densely packed thrombotic milieu. We report here that stimulated platelets switch their energy metabolism to aerobic glycolysis by modulating enzymes at key checkpoints in glucose metabolism. We found that aerobic glycolysis, in turn, accelerates flux through the pentose phos- phate pathway and supports platelet activation. Hence, reversing metabolic adaptations of platelets could be an effective alternative to conventional anti-platelet approaches, which are crippled by remarkable redundancy in platelet agonists and ensuing signaling pathways. In support of this hypoth- esis, small-molecule modulators of pyruvate dehydrogenase, pyruvate kinase M2 and glucose-6-phosphate dehydrogenase, all of which impede aerobic glycolysis and/or the pentose phosphate pathway, restrained the agonist-induced platelet responses ex vivo. These drugs, which include the anti-neoplastic candidate, dichloroacetate, and the Food and Drug Administration-approved dehydroepiandrosterone, profoundly impaired thrombosis in mice, thereby exhibiting potential as anti-thrombotic agents.
Introduction
Platelets play a prominent role in the pathophysiology of acute myocardial infarction and ischemic stroke, which are the major causes of mortality worldwide.1 Anti-platelet drugs remain the mainstay for the prevention of these catastrophic events. Nevertheless, the anti-platelet agents currently in vogue have limited efficacy in preventing thrombotic events without significantly raising bleeding risk.2 There is remarkable redundancy in potential agonists inducing platelet activation, as well as plasticity in the signaling paths downstream of these agonists. Patients on anti-platelet drugs that inhibit platelet responses to specific agonists continue to experience adverse thrombotic episodes, since other potential triggers and parallel signaling cascades can still activate platelets. Hence, it is vital to discover novel anti-platelet strategies to address these limitations.
In an intact vasculature, platelets are relatively inactive and are, therefore, described as ‘resting’. However, they are extremely responsive to any breach in the vessel wall and are highly efficient in sealing the defect. Following a break in endothelium, platelets interact with, and adhere to, the now exposed subendothe- lial matrix proteins, such as collagen, through their cell surface receptors. These receptor-ligand interactions initiate signaling cascades that lead to: (i) a change in the shape of platelets from discoid to ‘spiny-spheres’, (ii) platelet-platelet aggrega- tion through fibrinogen bridges connecting high-affinity integrins, and (iii) degran- ulation of platelet storage vesicles, the contents of which serve to amplify respons- es to vessel wall injury. A chain reaction of platelet activation and aggregate forma- tion, as well as conversion of fibrinogen to insoluble polymers of fibrin, culminates
Correspondence:
DEBABRATA DASH
ddash.biochem@gmail.com
Received: September 3, 2018. Accepted: October 30, 2018. Pre-published: October 31, 2018.
doi:10.3324/haematol.2018.205724
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/806
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