title: Involvement of the mitogen-activated protein kinase c-Jun NH2-terminal kinase 1 in thrombus formation.
abstract: 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.
authors.affiliation: Centre de Recherche Cardiovasculaire INSERM Lariboisière, U689-E4, Hôpital Lariboisière, 8 rue Guy Patin, 75010 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kauskot
authors.forename: Frédéric
authors.initials: F
authors.lastname: Adam
authors.forename: Alexandra
authors.initials: A
authors.lastname: Mazharian
authors.forename: Nadine
authors.initials: N
authors.lastname: Ajzenberg
authors.forename: Eliane
authors.initials: E
authors.lastname: Berrou
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bonnefoy
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rosa
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.forename: Marijke
authors.initials: M
authors.lastname: Bryckaert
mesh_terms: 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