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

Abstract

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 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.

• Authors: 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, Sandrine Horman
• Journal: Blood (Blood) Vol. 132 Issue 11 Pg. 1180-1192 (09 13 2018) ISSN: 1528-0020 [Electronic] United States
• PMID: 30018077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society of Hematology.

Chemical References

• AMPK alpha1 subunit, mouse
• AMP-Activated Protein Kinases
• ACC1 protein, mouse
• Acacb protein, mouse
• Acetyl-CoA Carboxylase

Topics

• AMP-Activated Protein Kinases (genetics, metabolism)
• Acetyl-CoA Carboxylase (genetics, metabolism)
• Animals
• Blood Platelets (enzymology, pathology)
• Gene Knock-In Techniques
• Mice
• Mice, Knockout
• Phosphorylation (genetics)
• Signal Transduction
• Thrombosis (enzymology, genetics, pathology)