Isotopically nonstationary 13C metabolic flux analysis in resting and activated human platelets

Sake, Cara L.; Metcalf, Alexander J.; Meagher, Michelle; Paola, Jorge Di; Neeves, Keith B.; Boyle, Nanette R.

doi:10.1016/j.ymben.2021.12.007

Cited by 12 publications

(8 citation statements)

References 59 publications

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“…5 However, it has also been reported that, dependency on glucose and fatty acids is higher than glutamine in platelets. 7 Since platelets metabolize nearly the entire glucose pool to lactate rather than routing it through mitochondrial tricarboxylic acid (TCA) cycle, 19 it is reasonably safe to posit that majority of mitochondrial ATP is sourced from oxidative lysis of fatty acids. This prompted us to determine the potential of targeting βoxidation of fatty acids as a novel antiplatelet strategy.…”

Section: Introductionmentioning

confidence: 99%

Fatty acid oxidation fuels agonist‐induced platelet activation and thrombus formation: Targeting β‐oxidation of fatty acids as an effective anti‐platelet strategy

et al. 2023

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Platelet mitochondria possess remarkable plasticity for oxidation of energy substrates, where metabolic dependency on glucose or fatty acids is higher than glutamine. Since platelets metabolize nearly the entire pool of glucose to lactate rather than fluxing through mitochondrial tricarboxylic acid cycle, we posit that majority of mitochondrial ATP, which is essential for platelet granule secretion and thrombus formation, is sourced from oxidation of fatty acids. We performed a comprehensive analysis of bioenergetics and function of stimulated platelets in the presence of etomoxir, trimetazidine and oxfenicine, three pharmacologically distinct inhibitors of β‐oxidation. Each of them significantly impaired oxidative phosphorylation in unstimulated as well as thrombin‐stimulated platelets leading to a small but consistent drop in ATP level in activated cells due to a lack of compensation from glycolytic ATP. Trimetazidine and oxfenicine attenuated platelet aggregation, P‐selectin externalization and integrin αIIbβ3 activation. Both etomoxir and trimetazidine impeded agonist‐induced dense granule release and platelet thrombus formation on collagen under arterial shear. The effect of inhibitors on platelet aggregation and dense granule release was dose‐ and incubation time‐ dependent with significant inhibition at higher doses and prolonged incubation times. Neither of the inhibitors could protect mice from collagen‐epinephrine‐induced pulmonary embolism or prolong mouse tail bleeding times. However, mice pre‐administered with etomoxir, trimetazidine and oxfenicine were protected from ferric chloride‐induced mesenteric thrombosis. In conclusion, β‐oxidation of fatty acids sustains ATP level in stimulated platelets and is therefore essential for energy‐intensive agonist‐induced platelet responses. Thus, fatty acid oxidation may constitute an attractive therapeutic target for novel antiplatelet agents.

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Section: Introductionmentioning

confidence: 99%

Fatty acid oxidation fuels agonist‐induced platelet activation and thrombus formation: Targeting β‐oxidation of fatty acids as an effective anti‐platelet strategy

et al. 2023

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“…The acetate present as a source of oxidizable fuel also provides additional buffering capacityits oxidation requires the conversion to an acidic form, removing an H + ion from the surrounding medium in the process. If the H + ion originated from carbonic acid, a bicarbonate ion would be generated, helping to retain levels of this physiological buffer in the medium [12,13]. The ACD-A anticoagulant used to collect platelets by apheresis does not contain either phosphate or acetate, with the platelets relying principally on the bicarbonate in the plasma to buffer the concentration of H + ions.…”

Section: Discussionmentioning

confidence: 99%

In vitro storage characteristics of neonatal platelet concentrates after addition of 20% PAS‐E

2022

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Background and Objectives: An observed decline in end-of-storage pH in plateletpheresis-derived platelet concentrates for neonatal use suspended in 100% autologous plasma was expected to be reversed by the addition of a platelet additive solution, (PAS)-E, increasing unit volume by approximately 20%. This study determined the impact on other in vitro storage parameters to ensure the expected increase in pH did not mask an adverse impact on component quality. Study Design and Methods:For each replicate, one of a pair from a double adult dose plateletpheresis collection had approximately 50 ml of PAS-E added on Day 3 of storage. Its unmodified twin served as a control. Each adult dose was split into four neonatal storage packs and tested on Days 3, 6, 7 and 8. Three of 12 replicates were from donors with a history of low pH at end of storage and reflected the worst-case scenario for the new components. A further experiment evaluated whether any differences were simply due to the increased unit volume.Results: In the nine randomly selected collections, pH on Day 8 was approximately 0.4 units higher in the test units. Platelet activation tended to be lower, with CD62P surface expression on Day 8 of 54.6 AE 9.9% compared to 65.8 AE 10.7% for controls (p < 0.001). Test units from donors with historically low pH retained pH 22 C levels above 6.8 compared to controls (<6.4 on Day 8). Conclusion:The addition of 20% PAS-E by volume increased the buffering capacity of the units whilst maintaining other in vitro storage characteristics.

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“…Some studies report a switch to aerobic glycolysis (the conversion of glucose to lactate in the presence of oxygen) upon platelet activation [ 35 , 38 , 39 ]. Other studies have considered the switch to oxidative metabolism a fundamental requirement for the transition to an activated state [ 36 , 38 , 40 ]. Platelets’ metabolic substrate preferences are not yet completely clear.…”

Section: Introductionmentioning

confidence: 99%

“…Some pathological conditions, such as asthma, are associated with abnormal clot architecture and lower clot retraction rates [ 49 ]. Fatty acid (FA) β-oxidation supplies most ATP in stimulated platelets during granule secretion and thrombus formation [ 41 ] and can compensate for a reduction in glucose availability [ 40 , 44 ]. However, the inhibition of FA oxidation and/or glutaminolysis cannot prevent platelet aggregation [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Platelet Metabolic Flexibility: A Matter of Substrate and Location

Ravera

Signorello

Panfoli

2023

Cells

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Platelets are cellular elements that are physiologically involved in hemostasis, inflammation, thrombotic events, and various human diseases. There is a link between the activation of platelets and their metabolism. Platelets possess considerable metabolic versatility. Although the role of platelets in hemostasis and inflammation is known, our current understanding of platelet metabolism in terms of substrate preference is limited. Platelet activation triggers an oxidative metabolism increase to sustain energy requirements better than aerobic glycolysis alone. In addition, platelets possess extra-mitochondrial oxidative phosphorylation, which could be one of the sources of chemical energy required for platelet activation. This review aims to provide an overview of flexible platelet metabolism, focusing on the role of metabolic compartmentalization in substrate preference, since the metabolic flexibility of stimulated platelets could depend on subcellular localization and functional timing. Thus, developing a detailed understanding of the link between platelet activation and metabolic changes is crucial for improving human health.

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Isotopically nonstationary 13C metabolic flux analysis in resting and activated human platelets

Cited by 12 publications

References 59 publications

Fatty acid oxidation fuels agonist‐induced platelet activation and thrombus formation: Targeting β‐oxidation of fatty acids as an effective anti‐platelet strategy

Fatty acid oxidation fuels agonist‐induced platelet activation and thrombus formation: Targeting β‐oxidation of fatty acids as an effective anti‐platelet strategy

In vitro storage characteristics of neonatal platelet concentrates after addition of 20% PAS‐E

Platelet Metabolic Flexibility: A Matter of Substrate and Location

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