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AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation
Lepropre, Sophie Kautbally, Shakeel Octave, Marie Ginion, Audrey Onselaer, Marie-Blanche Steinberg, Gregory R. Kemp, Bruce E. Hego, Alexandre Wéra, Odile Brouns, Sanne
Lepropre, Sophie
Kautbally, Shakeel
Octave, Marie
Ginion, Audrey
Onselaer, Marie-Blanche
Steinberg, Gregory R.
Kemp, Bruce E.
Hego, Alexandre
Wéra, Odile
Brouns, Sanne
Author
Lepropre, Sophie
Kautbally, Shakeel
Octave, Marie
Ginion, Audrey
Onselaer, Marie-Blanche
Steinberg, Gregory R.
Kemp, Bruce E.
Hego, Alexandre
Wéra, Odile
Brouns, Sanne
Swieringa, Frauke
Giera, Martin
Darley-Usmar, Victor M.
Ambroise, Jérôme
Guigas, Bruno
Heemskerk, Johan
Bertrand, Luc
Oury, Cécile
Beauloye, Christophe
Horman, Sandrine
Kautbally, Shakeel
Octave, Marie
Ginion, Audrey
Onselaer, Marie-Blanche
Steinberg, Gregory R.
Kemp, Bruce E.
Hego, Alexandre
Wéra, Odile
Brouns, Sanne
Swieringa, Frauke
Giera, Martin
Darley-Usmar, Victor M.
Ambroise, Jérôme
Guigas, Bruno
Heemskerk, Johan
Bertrand, Luc
Oury, Cécile
Beauloye, Christophe
Horman, Sandrine
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.
Keywords
AMPK-ACC signaling, lipids, thrombin stimulation, collagen stimulation, acetyl-CoA carboxylase (ACC), ACC phosphorylation
Date
2018
Type
Journal article
Journal
Blood
Book
Volume
132
Issue
11
Page Range
1180-1192
Article Number
ACU Department
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled