TY - JOUR
T1 - AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation
AU - Lepropre, Sophie
AU - Kautbally, Shakeel
AU - Octave, Marie
AU - Ginion, Audrey
AU - Onselaer, Marie-Blanche
AU - Steinberg, Gregory R.
AU - Kemp, Bruce E.
AU - Hego, Alexandre
AU - Wera, Odile
AU - Brouns, Sanne
AU - Swieringa, Frauke
AU - Giera, Martin
AU - Darley-Usmar, Victor M.
AU - Ambroise, Jerome
AU - Guigas, Bruno
AU - Heemskerk, Johan
AU - Bertrand, Luc
AU - Oury, Cecile
AU - Beauloye, Christophe
AU - Horman, Sandrine
PY - 2018/9/13
Y1 - 2018/9/13
N2 - AMP-activated protein kinase (AMPK) a1 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.
AB - AMP-activated protein kinase (AMPK) a1 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.
KW - ACETYL-COA CARBOXYLASE
KW - STIMULATED HUMAN PLATELETS
KW - GLYCOPROTEIN-VI
KW - ARTERIAL THROMBOSIS
KW - IN-VIVO
KW - PHOSPHORYLATION SITES
KW - GRANULE RELEASE
KW - MUTANT MICE
KW - FATTY-ACID
KW - ACTIVATION
U2 - 10.1182/blood-2018-02-831503
DO - 10.1182/blood-2018-02-831503
M3 - Article
C2 - 30018077
SN - 0006-4971
VL - 132
SP - 1180
EP - 1192
JO - Blood
JF - Blood
IS - 11
ER -