Involvement of the mitogen-activated protein kinase c-Jun NH2-terminal kinase 1 in thrombus formation.
The involvement of the mitogen-activated protein kinase c-Jun NH2-terminal kinase-1 (JNK1) has never been investigated in hemostasis and thrombosis. Using two JNK inhibitors (SP600125 and 6o), we have demonstrated that JNK1 is involved in collagen-induced platelet aggregation dependent on ADP. In these conditions, JNK1 activation requires the coordinated signaling pathways of collagen receptors (alpha2beta1 and glycoprotein (GP)VI) and ADP. In contrast, JNK1 is not required for platelet adhesion on a collagen matrix in static or blood flow conditions (300-1500 s(-1)) involving collagen receptors (alpha2beta1 and GPVI). Importantly, at 1500 s(-1), JNK1 acts on thrombus formation on a collagen matrix dependent on GPIb-von Willebrand factor (vWF) interaction but not ADP receptor activation. This is confirmed by the involvement of JNK1 in shear-induced platelet aggregation at 4000 s(-1). We also provide evidence during rolling and adhesion of platelets to vWF that platelet GPIb-vWF interaction triggers alphaIIbbeta3 activation in a JNK1-dependent manner. This was confirmed with a Glanzmann thrombastenic patient lacking alphaIIbbeta3. Finally, in vivo, JNK1 is involved in arterial but not in venular thrombosis in mice. Overall, our in vitro studies define a new role of JNK1 in thrombus formation in flowing blood that is relevant to thrombus development in vivo.
Kauskot
Alexandre
A
Centre de Recherche Cardiovasculaire INSERM Lariboisière, U689-E4, Hôpital Lariboisière, 8 rue Guy Patin, 75010 Paris, France.
Adam
Frédéric
F
Mazharian
Alexandra
A
Ajzenberg
Nadine
N
Berrou
Eliane
E
Bonnefoy
Arnaud
A
Rosa
Jean-Philippe
JP
Hoylaerts
Marc F
MF
Bryckaert
Marijke
M
D000818:Animals; D003094:Collagen / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D013915:Thrombasthenia / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism