Platelet JNK1 is involved in secretion and thrombus formation.
The role of c-Jun NH(2)-terminal kinase 1 (JNK1) in hemostasis and thrombosis remains unclear. We show here, with JNK1-deficient (JNK1(-/-)) mice, that JNK1 plays an important role in platelet biology and thrombus formation. In tail-bleeding assays, JNK1(-/-) mice exhibited longer bleeding times than wild-type mice (396 +/- 39 seconds vs 245 +/- 32 seconds). We also carried out in vitro whole-blood perfusion assays on a collagen matrix under arterial shear conditions. Thrombus formation was significantly reduced for JNK1(-/-) platelets (51%). In an in vivo model of thrombosis induced by photochemical injury to cecum vessels, occlusion times were 4.3 times longer in JNK1(-/-) arterioles than in wild-type arterioles. Moreover, in vitro studies carried out in platelet aggregation conditions demonstrated that, at low doses of agonists, platelet secretion was impaired in JNK1(-/-) platelets, leading to altered integrin alphaIIbbeta3 activation and reduced platelet aggregation, via a mechanism involving protein kinase C. JNK1 thus appears to be essential for platelet secretion in vitro, consistent with its role in thrombus growth in vivo. Finally, we showed that ERK2 and another isoform of JNK affect platelet aggregation through 2 pathways, one dependent and another independent of JNK1.
Adam
Frédéric
F
Inserm U770, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
Kauskot
Alexandre
A
Nurden
Paquita
P
Sulpice
Eric
E
Hoylaerts
Marc F
MF
Davis
Roger J
RJ
Rosa
Jean-Philippe
JP
Bryckaert
Marijke
M
D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D005434:Flow Cytometry; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D010974:Platelet Aggregation; D010976:Platelet Count; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011493:Protein Kinase C; D048055:Mitogen-Activated Protein Kinase 8