TY - JOUR
T1 - Platelet CD40L Modulates Thrombus Growth Via Phosphatidylinositol 3-Kinase beta, and Not Via CD40 and I kappa B Kinase alpha
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, L
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
Y1 - 2015/6
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 alpha(IIb)beta(3) activation and a-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 Pik3cb(R/R) platelets or by inhibiting phosphatidylinositol 3-kinase beta(PI3K beta). Addition of CD40L also enhanced collagen-induced Akt phosphorylation, which was again antagonized by absence or inhibition of PI3K beta. Finally, platelets from Chuk1(A/A)Apoe(-/-)mice deficient in I kappa B kinase alpha (IKK alpha), implicated in CD40 signaling to nuclear factor (NF)kappa B, showed unchanged responses to CD40L in aggregation or thrombus formation. Conclusions-Under atherogenic conditions, CD40L enhances collagen-induced platelet-platelet interactions by supporting integrin alpha(IIb)beta(3) activation, secretion and thrombus growth via PI3K beta, but not via CD40 and IKK alpha/NF kappa B. 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 alpha(IIb)beta(3) activation and a-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 Pik3cb(R/R) platelets or by inhibiting phosphatidylinositol 3-kinase beta(PI3K beta). Addition of CD40L also enhanced collagen-induced Akt phosphorylation, which was again antagonized by absence or inhibition of PI3K beta. Finally, platelets from Chuk1(A/A)Apoe(-/-)mice deficient in I kappa B kinase alpha (IKK alpha), implicated in CD40 signaling to nuclear factor (NF)kappa B, showed unchanged responses to CD40L in aggregation or thrombus formation. Conclusions-Under atherogenic conditions, CD40L enhances collagen-induced platelet-platelet interactions by supporting integrin alpha(IIb)beta(3) activation, secretion and thrombus growth via PI3K beta, but not via CD40 and IKK alpha/NF kappa B. This role of CD40L exceeds the no more than modest role of CD40 in thrombus formation.
KW - atherosclerosis
KW - atherothrombosis
KW - blood platelets
KW - CD40
KW - CD40 ligand
KW - signaling pathways
KW - signal transduction
KW - thrombosis
U2 - 10.1161/ATVBAHA.114.305127
DO - 10.1161/ATVBAHA.114.305127
M3 - Article
C2 - 25908768
SN - 1079-5642
VL - 35
SP - 1374
EP - 1381
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 6
ER -