Dual role of platelet protein kinase C in thrombus formation: stimulation of pro-aggregatory and suppression of procoagulant activity in platelets.
Protein kinase C (PKC) isoforms regulate many platelet responses in a still incompletely understood manner. Here we investigated the roles of PKC in the platelet reactions implicated in thrombus formation as follows: secretion aggregate formation and coagulation-stimulating activity, using inhibitors with proven activity in plasma. In human and mouse platelets, PKC regulated aggregation by mediating secretion and contributing to alphaIIbbeta3 activation. Strikingly, PKC suppressed Ca(2+) signal generation and Ca(2+)-dependent exposure of procoagulant phosphatidylserine. Furthermore, under coagulant conditions, PKC suppressed the thrombin-generating capacity of platelets. In flowing human and mouse blood, PKC contributed to platelet adhesion and controlled secretion-dependent thrombus formation, whereas it down-regulated Ca(2+) signaling and procoagulant activity. In murine platelets lacking G(q)alpha, where secretion reactions were reduced in comparison with wild type mice, PKC still positively regulated platelet aggregation and down-regulated procoagulant activity. We conclude that platelet PKC isoforms have a dual controlling role in thrombus formation as follows: (i) by mediating secretion and integrin activation required for platelet aggregation under flow, and (ii) by suppressing Ca(2+)-dependent phosphatidylserine exposure, and consequently thrombin generation and coagulation. This platelet signaling protein is the first one identified to balance the pro-aggregatory and procoagulant functions of thrombi.
Strehl
Amrei
A
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University of Maastricht, 6200 MD Maastricht, The Netherlands.
Munnix
Imke C A
IC
Kuijpers
Marijke J E
MJ
van der Meijden
Paola E J
PE
Cosemans
Judith M E M
JM
Feijge
Marion A H
MA
Nieswandt
Bernhard
B
Heemskerk
Johan W M
JW
D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D033081:Shear Strength; D013927:Thrombosis / Q000209:etiology*
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium