TY - JOUR
T1 - Platelet CD40L Modulates Thrombus Growth Via Phosphatidylinositol 3-Kinase β, and Not Via CD40 and IκB Kinase α
AU - Kuijpers, Marijke J.E.
AU - Mattheij, Nadine J.A.
AU - Cipolla, Lina
AU - Van Geffen, Johanna P.
AU - Lawrence, Toby
AU - Donners, Marjo M.P.C.
AU - Boon, Louis
AU - Lievens, Dirk
AU - Torti, Mauro
AU - Noels, Heidi
AU - Gerdes, Norbert
AU - Cosemans, Judith M.E.M.
AU - Lutgens, Esther
AU - Heemskerk, Johan W.M.
PY - 2015/6/27
Y1 - 2015/6/27
N2 - Objective - To investigate the roles and signaling pathways of CD40L and CD40 in platelet-platelet interactions and thrombus formation under conditions relevant for atherothrombosis. Approach and Results - Platelets from mice prone to atherosclerosis lacking CD40L (Cd40lg-/-Apoe-/-) showed diminished αIIbβ3activation and α-granule secretion in response to glycoprotein VI stimulation, whereas these responses of CD40-deficient platelets (Cd40-/-Apoe-/-) were not decreased. Using blood from Cd40lg-/-Apoe-/- and Cd40-/-Apoe-/- mice, the glycoprotein VI-dependent formation of dense thrombi was impaired on atherosclerotic plaque material or on collagen, in comparison with Apoe-/- blood. In all genotypes, addition of CD40L to the blood enhanced the growth of dense thrombi on plaques and collagen. Similarly, CD40L enhanced glycoprotein VI-induced platelet aggregation, even with platelets deficient in CD40. This potentiation was antagonized in Pik3cbR/R platelets or by inhibiting phosphatidylinositol 3-kinase β (PI3Kβ). Addition of CD40L also enhanced collagen-induced Akt phosphorylation, which was again antagonized by absence or inhibition of PI3Kβ. Finally, platelets from Chuk1A/AApoe-/- mice deficient in IκB kinase α (IKKα), implicated in CD40 signaling to nuclear factor (NF) κB, showed unchanged responses to CD40L in aggregation or thrombus formation. Conclusions - Under atherogenic conditions, CD40L enhances collagen-induced platelet-platelet interactions by supporting integrin αIIbβ3activation, secretion and thrombus growth via PI3Kβ, but not via CD40 and IKKα/NFκB. This role of CD40L exceeds the no more than modest role of CD40 in thrombus formation.
AB - Objective - To investigate the roles and signaling pathways of CD40L and CD40 in platelet-platelet interactions and thrombus formation under conditions relevant for atherothrombosis. Approach and Results - Platelets from mice prone to atherosclerosis lacking CD40L (Cd40lg-/-Apoe-/-) showed diminished αIIbβ3activation and α-granule secretion in response to glycoprotein VI stimulation, whereas these responses of CD40-deficient platelets (Cd40-/-Apoe-/-) were not decreased. Using blood from Cd40lg-/-Apoe-/- and Cd40-/-Apoe-/- mice, the glycoprotein VI-dependent formation of dense thrombi was impaired on atherosclerotic plaque material or on collagen, in comparison with Apoe-/- blood. In all genotypes, addition of CD40L to the blood enhanced the growth of dense thrombi on plaques and collagen. Similarly, CD40L enhanced glycoprotein VI-induced platelet aggregation, even with platelets deficient in CD40. This potentiation was antagonized in Pik3cbR/R platelets or by inhibiting phosphatidylinositol 3-kinase β (PI3Kβ). Addition of CD40L also enhanced collagen-induced Akt phosphorylation, which was again antagonized by absence or inhibition of PI3Kβ. Finally, platelets from Chuk1A/AApoe-/- mice deficient in IκB kinase α (IKKα), implicated in CD40 signaling to nuclear factor (NF) κB, showed unchanged responses to CD40L in aggregation or thrombus formation. Conclusions - Under atherogenic conditions, CD40L enhances collagen-induced platelet-platelet interactions by supporting integrin αIIbβ3activation, secretion and thrombus growth via PI3Kβ, but not via CD40 and IKKα/NFκB. This role of CD40L exceeds the no more than modest role of CD40 in thrombus formation.
KW - CD40
KW - CD40 ligand
KW - atherosclerosis
KW - atherothrombosis
KW - blood platelets
KW - signal transduction
KW - signaling pathways
KW - thrombosis
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U2 - 10.1161/ATVBAHA.114.305127
DO - 10.1161/ATVBAHA.114.305127
M3 - Article
C2 - 25908768
AN - SCOPUS:84933042246
SN - 1079-5642
VL - 35
SP - 1374
EP - 1381
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 6
ER -