Key result
PKCdelta inhibition regulates platelet secretion and TXA2 generation but does not affect in vivo thrombosis.
PKCdelta differentially regulates platelet functional responses in vitro but its deficiency does not affect in vivo thrombus formation.
PKCδ inhibition does not affect in vivo thrombosis despite platelet effects in vitro; leaves open its role as antithrombotic target.
OBJECTIVE: Protein Kinase C delta (PKCdelta) 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 PKCdelta in platelets. METHODS AND RESULTS: We evaluated the role of PKCdelta in platelets using two approaches--pharmacological and molecular genetic approach. In human platelets pretreated with isoform selective antagonistic RACK peptide (delta V1-1)TAT, and in the murine platelets lacking PKCdelta, 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 PKCdelta. However, PKCdelta had a small effect on platelet P-selectin expression. Calcium- and PKC-dependent pathways independently activate fibrinogen receptor in platelets. When calcium pathways are blocked by dimethyl-BAPTA, AYPGKF-induced aggregation in PKCdelta null mouse platelets and in human platelets pretreated with (delta V1-1)TAT, was inhibited. In a FeCl3-induced injury in vivo thrombosis model, PKCdelta-/- mice occluded similar to their wild-type littermates. CONCLUSIONS: Hence, we conclude that PKCdelta differentially regulates platelet functional responses such as dense granule secretion and TXA2 generation downstream of PARs and GPVI receptors, but PKCdelta deficiency does not affect the thrombus formation in vivo.
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Chari et al. (2009) studied Platelet function and thrombosis. PKCdelta inhibition or deficiency vs. Wild-type or untreated platelets was evaluated on Platelet functional responses (dense granule secretion, TXA2 generation, aggregation, and in vivo thrombosis). PKCdelta inhibition or deficiency differentially regulates platelet dense granule secretion and TXA2 generation downstream of PARs and GPVI receptors, but does not affect in vivo thrombus formation.
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