Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?
Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?
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血小板代谢靶向对抗血栓形成：新范式的曙光？
DOI：
10.1093/cvr/cvad149
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发表时间：
2023
影响因子：
10.8
通讯作者：
Chauhan,AnilK
中科院分区：
文献类型：
--
作者：
Flora,GaganD;Nayak,ManasaK;Ghatge,Madankumar;Chauhan,AnilK
目前临床上使用的抗血栓治疗针对的是凝血途径或血小板激活受体(P2Y12或GPIIb/IIIa)，以及通过阿司匹林的环氧合酶(COX)酶。然而，它们与出血风险有关，不适合长期使用。因此，需要新的策略，以最小的出血风险提供广泛的保护，防止血小板激活。无论激动剂刺激的性质如何，血小板激活都是一个能量密集型和由ATP驱动的过程，其特征是相对于氧化磷酸化(OXPHOS)，代谢转换为高速率的有氧糖酵解。因此，近年来，人们对研究靶向血小板代谢途径，特别是有氧糖酵解和OXPHOS是否可以调节其激活，从而预防血栓形成产生了相当大的兴趣。这篇综述简要讨论了驱动血小板代谢灵活性的代谢底物的选择。我们已经全面阐明了有氧糖酵解在促进血小板激活中的相关性，以及触发这种从OXPHOS转换的潜在分子机制。我们已经提供了针对重要的代谢检查点，如丙酮酸脱氢酶(PDKs)和丙酮酸激酶M2(PKM2)的抗血小板作用的详细描述，这些检查点优先驱动丙酮酸流向有氧糖酵解。此外，我们还讨论了线粒体中脂肪酸和谷氨酰胺氧化的作用，以及它们随后在驱动OXPHOS和血小板激活中的作用。尽管靶向血小板代谢调节机制以防止其激活的方法仍处于初级阶段，但越来越多的证据突显了其作为一种潜在的新的抗血栓策略的益处。
Current antithrombotic therapies used in clinical settings target either the coagulation pathways or platelet activation receptors (P2Y12or 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.