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AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation.

ABSTRACT: AMP-activated protein kinase (AMPK) ?1 is activated in platelets on thrombin or collagen stimulation, and as a consequence, phosphorylates and inhibits acetyl-CoA carboxylase (ACC). Because ACC is crucial for the synthesis of fatty acids, which are essential for platelet activation, we hypothesized that this enzyme plays a central regulatory role in platelet function. To investigate this, we used a double knock-in (DKI) mouse model in which the AMPK phosphorylation sites Ser79 on ACC1 and Ser212 on ACC2 were mutated to prevent AMPK signaling to ACC. Suppression of ACC phosphorylation promoted injury-induced arterial thrombosis in vivo and enhanced thrombus growth ex vivo on collagen-coated surfaces under flow. After collagen stimulation, loss of AMPK-ACC signaling was associated with amplified thromboxane generation and dense granule secretion. ACC DKI platelets had increased arachidonic acid-containing phosphatidylethanolamine plasmalogen lipids. In conclusion, AMPK-ACC signaling is coupled to the control of thrombosis by specifically modulating thromboxane and granule release in response to collagen. It appears to achieve this by increasing platelet phospholipid content required for the generation of arachidonic acid, a key mediator of platelet activation.

SUBMITTER: Lepropre S

PROVIDER: S-EPMC6238154 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation.

Lepropre Sophie S Kautbally Shakeel S Octave Marie M Ginion Audrey A Onselaer Marie-Blanche MB Steinberg Gregory R GR Kemp Bruce E BE Hego Alexandre A Wéra Odile O Brouns Sanne S Swieringa Frauke F Giera Martin M Darley-Usmar Victor M VM Ambroise Jérôme J Guigas Bruno B Heemskerk Johan J Bertrand Luc L Oury Cécile C Beauloye Christophe C Horman Sandrine S

Blood 20180717 11

AMP-activated protein kinase (AMPK) α1 is activated in platelets on thrombin or collagen stimulation, and as a consequence, phosphorylates and inhibits acetyl-CoA carboxylase (ACC). Because ACC is crucial for the synthesis of fatty acids, which are essential for platelet activation, we hypothesized that this enzyme plays a central regulatory role in platelet function. To investigate this, we used a double knock-in (DKI) mouse model in which the AMPK phosphorylation sites Ser79 on ACC1 and Ser212 ...[more]

PMID: 30018077

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AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation.

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AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation.

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