Kulkarni 2018 Haematologica

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Kulkarni PP, Tiwari A, Singh N, Gautam D, Sonkar VK, Agarwal V, Dash D (2018) Aerobic glycolysis fuels platelet activation: small-molecule modulators of platelet metabolism as anti-thrombotic agents. Haematologica [Epub ahead of print].

» PMID: 30381300 Open Access

Kulkarni PP, Tiwari A, Singh N, Gautam D, Sonkar VK, Agarwal V, Dash D (2018) Haematologica

Abstract: Platelets are critical to arterial thrombosis that underlies myocardial infarction and stroke. Activated platelets, regardless of nature of stimulus, initiate energy-intensive processes that sustain thrombus, while adapting to potential adversities of hypoxia and nutrient deprivation within the densely packed thrombus 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 aerobic glycolysis to, in turn, accelerate flux through pentose phosphate pathway and support platelet activation. Hence, reversing metabolic adaptations of platelets could be an effective alternative to conventional anti-platelet approaches that are crippled by remarkable redundancy in platelet agonists and ensuing signaling pathways. Concurring with this proposition, small-molecule modulators of pyruvate dehydrogenase, pyruvate kinase M2 and glucose-6-phosphate dehydrogenase, all of which disfavor aerobic glycolysis and/or pentose phosphate pathway, restrained the agonist-induced platelet responses ex vivo. These drugs, which include the anti-neoplastic candidate - dichloroacetate, and FDA-approved dehydroepiandrosterone, profoundly impaired thrombosis in mice, thereby exhibiting potential as anti-thrombotic agents.

Keywords: Antithrombotic Therapy, Arterial Thrombosis, Molecular Pharmacology, Platelets, Venous Thrombosis Bioblast editor: Plangger M O2k-Network Lab: IN Varanasi Dash D


Labels: MiParea: Respiration, Pharmacology;toxicology 


Organism: Human  Tissue;cell: Platelet  Preparation: Intact cells 


Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 

Labels, 2018-12