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Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation.

ABSTRACT: OBJECTIVE:On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand glucose metabolism in platelets. APPROACH AND RESULTS:Platelet-specific knockout of GLUT3 was generated by crossing mice harboring GLUT3 floxed allele to a PF4 (platelet factor 4)-driven Cre recombinase. In platelets, GLUT3 is localized primarily on ?-granule membranes and under basal conditions facilitates glucose uptake into ?-granules to be used for glycolysis. After activation, platelets degranulate and GLUT3 translocates to the plasma membrane, which is responsible for activation-mediated increased glucose uptake. In vivo, loss of GLUT3 in platelets increased survival in a collagen/epinephrine model of pulmonary embolism, and in a K/BxN model of autoimmune inflammatory disease, platelet-specific GLUT3 knockout mice display decreased disease progression. Mechanistically, loss of GLUT3 decreased platelet degranulation, spreading, and clot retraction. Decreased ?-granule degranulation is due in part to an impaired ability of GLUT3 to potentiate exocytosis. CONCLUSIONS:GLUT3-mediated glucose utilization and glycogenolysis in platelets promotes ?-granule release, platelet activation, and postactivation functions.

SUBMITTER: Fidler TP

PROVIDER: S-EPMC5570649 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation.

Fidler Trevor P TP Middleton Elizabeth A EA Rowley Jesse W JW Boudreau Luc H LH Campbell Robert A RA Souvenir Rhonda R Funari Trevor T Tessandier Nicolas N Boilard Eric E Weyrich Andrew S AS Abel E Dale ED

Arteriosclerosis, thrombosis, and vascular biology 20170629 9

<h4>Objective</h4>On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand ...[more]

PMID: 28663252

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Project description:BackgroundUncontrolled microglial activation contributes to the pathogenesis of various neurodegenerative diseases. Previous studies have shown that proinflammatory microglia are powered by glycolysis, which relays on high levels of glucose uptake. This study aimed to understand how glucose uptake is facilitated in active microglia and whether microglial activation can be controlled by restricting glucose uptake.MethodsPrimary murine brain microglia, BV2 cells and the newly established microglial cell line B6M7 were treated with LPS (100?ng/ml)?+?IFN? (100?ng/ml) or IL-4 (20?ng/ml) for 24?h. The expression of glucose transporters (GLUTs) was examined by PCR and Western blot. Glucose uptake by microglia was inhibited using the GLUT1-specific inhibitor STF31. The metabolic profiles were tested using the Glycolysis Stress Test and Mito Stress Test Kits using the Seahorse XFe96 Analyser. Inflammatory gene expression was examined by real-time RT-PCR and protein secretion by cytokine beads array. The effect of STF31 on microglial activation and neurodegeneraion was further tested in a mouse model of light-induced retinal degeneration.ResultsThe mRNA and protein of GLUT1, 3, 4, 5, 6, 8, 9, 10, 12, and 13 were detected in microglia. The expression level of GLUT1 was the highest among all GLUTs detected. LPS?+?IFN? treatment further increased GLUT1 expression. STF31 dose-dependently reduced glucose uptake and suppressed Extracellular Acidification Rate (ECAR) in naïve, M(LPS?+?IFN?) and M(IL-4) microglia. The treatment also prevented the upregulation of inflammatory cytokines including TNF?, IL-1?, IL-6, and CCL2 in M(LPS?+?IFN?) microglia. Interestingly, the Oxygen Consumption Rates (OCR) was increased in M(LPS?+?IFN?) microglia but reduced in M(IL-4) microglia by STF31 treatment. Intraperitoneal injection of STF31 reduced light-induced microglial activation and retinal degeneration.ConclusionGlucose uptake in microglia is facilitated predominately by GLUT1, particularly under inflammatory conditions. Targeting GLUT1 could be an effective approach to control neuroinflammation.

Project description:AimsAdverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported.Methods and resultsHere, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbβ3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway.ConclusionWe provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.

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Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation.

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Glucose Transporter 3 Potentiates Degranulation and Is Required for Platelet Activation.

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