Protein Kinase C Differentially Regulates Platelet Functional Responses

Objective—Protein Kinase C delta (PKC ) is expressed in platelets and activated downstream of protease-activated receptors (PAR)s and glycoprotein VI (GPVI) receptors. The purpose of this study was to investigate the role of PKC in platelets. Methods and Results—We evaluated the role of PKC in platelets using two approaches—pharmacological and molecular genetic approach. In human platelets pretreated with isoform selective antagonistic RACK peptide ( V1-1)TAT, and in the murine platelets lacking PKC , PAR4-mediated dense granule secretion was inhibited, whereas GPVI-mediated dense granule secretion was potentiated. These effects were statistically significant in the absence and presence of thromboxane A2 (TXA2). Furthermore, TXA2 generation was differentially regulated by PKC . However, PKC had a small effect on platelet P-selectin expression. Calciumand PKC-dependent pathways independently activate fibrinogen receptor in platelets. When calcium pathways are blocked by dimethyl-BAPTA, AYPGKF-induced aggregation in PKC null mouse platelets and in human platelets pretreated with ( V1-1)TAT, was inhibited. In a FeCl3-induced injury in vivo thrombosis model, PKC / mice occluded similar to their wild-type littermates. Conclusions—Hence, we conclude that PKC differentially regulates platelet functional responses such as dense granule secretion and TXA2 generation downstream of PARs and GPVI receptors, but PKC deficiency does not affect the thrombus formation in vivo. (Arterioscler Thromb Vasc Biol. 2009;29:699-705.)