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AMPK-ACC signaling modulates platelet phospholipids content and potentiates platelet function and thrombus formation

Sophie Lepropre, Shakeel Kautbally, Marie Octave, Audrey Ginion, Marie-Blanche Onselaer, Gregory R. Steinberg, Bruce E. Kemp, Alexandre Hego, Odile Wéra, Sanne Brouns, Frauke Swieringa, Martin Giera, Victor M. Darley-Usmar, Jérôme Ambroise, Bruno Guigas, Johan Heemskerk, Luc Bertrand, Cécile Oury, Christophe Beauloye and Sandrine Horman

Key points

  • AMPK-ACC signaling in platelets is a key mechanism regulating primary hemostasis and arterial thrombosis.

  • AMPK-ACC signaling controls collagen-induced TXA2 generation and dense granule release by modulating platelet phospholipid content.

Abstract

AMP-activated protein kinase (AMPK) α1 is activated in platelets upon thrombin or collagen stimulation, and as consequence phosphorylates and inhibits acetyl-CoA carboxylase (ACC). Since 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.

  • Submitted February 5, 2018.
  • Accepted July 8, 2018.