Journal article
Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?
Cardiovascular research, Vol.119(15), pp.2497-2507
11/2023
DOI: 10.1093/cvr/cvad149
PMCID: PMC10676458
PMID: 37706546
Abstract
Abstract Current antithrombotic therapies used in clinical settings target either the coagulation pathways or platelet activation receptors (P2Y12 or GPIIb/IIIa), as well as the cyclooxygenase (COX) enzyme through aspirin. However, they are associated with bleeding risk and are not suitable for long-term use. Thus, novel strategies which provide broad protection against platelet activation with minimal bleeding risks are required. Regardless of the nature of agonist stimulation, platelet activation is an energy-intensive and ATP-driven process characterized by metabolic switching toward a high rate of aerobic glycolysis, relative to oxidative phosphorylation (OXPHOS). Consequently, there has been considerable interest in recent years in investigating whether targeting metabolic pathways in platelets, especially aerobic glycolysis and OXPHOS, can modulate their activation, thereby preventing thrombosis. This review briefly discusses the choices of metabolic substrates available to platelets that drive their metabolic flexibility. We have comprehensively elucidated the relevance of aerobic glycolysis in facilitating platelet activation and the underlying molecular mechanisms that trigger this switch from OXPHOS. We have provided a detailed account of the antiplatelet effects of targeting vital metabolic checkpoints such as pyruvate dehydrogenase kinases (PDKs) and pyruvate kinase M2 (PKM2) that preferentially drive the pyruvate flux to aerobic glycolysis. Furthermore, we discuss the role of fatty acids and glutamine oxidation in mitochondria and their subsequent role in driving OXPHOS and platelet activation. While the approach of targeting metabolic regulatory mechanisms in platelets to prevent their activation is still in a nascent stage, accumulating evidence highlights its beneficial effects as a potentially novel antithrombotic strategy.
Details
- Title: Subtitle
- Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?
- Creators
- Gagan D Flora - University of IowaManasa K Nayak - University of IowaMadankumar Ghatge - University of IowaAnil K Chauhan - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.119(15), pp.2497-2507
- Publisher
- Oxford University Press (OUP)
- DOI
- 10.1093/cvr/cvad149
- PMID
- 37706546
- PMCID
- PMC10676458
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000065, name: National Institute of Neurological Disorders and Stroke; DOI: 10.13039/100000968, name: American Heart Association
- Language
- English
- Electronic publication date
- 09/14/2023
- Date published
- 11/2023
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984466559702771
Metrics
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