Abstract
Platelets are central players in atherothrombosis development in coronary artery disease. The PKC family provides important intracellular mechanisms for regulating platelet activity, and platelets express several members of this family, including the classical isoforms PKCalpha and PKCbeta and novel isoforms PKCdelta and PKCtheta. Here, we used a genetic approach to definitively demonstrate the role played by PKCalpha in regulating thrombus formation and platelet function. Thrombus formation in vivo was attenuated in Prkca-/- mice, and PKCalpha was required for thrombus formation in vitro, although this PKC isoform did not regulate platelet adhesion to collagen. The ablation of in vitro thrombus formation in Prkca-/- platelets was rescued by the addition of ADP, consistent with the key mechanistic finding that dense-granule biogenesis and secretion depend upon PKCalpha expression. Furthermore, defective platelet aggregation in response to either collagen-related peptide or thrombin could be overcome by an increase in agonist concentration. Evidence of overt bleeding, including gastrointestinal and tail bleeding, was not seen in Prkca-/- mice. In summary, the effects of PKCalpha ablation on thrombus formation and granule secretion may implicate PKCalpha as a drug target for antithrombotic therapy.
Highlights
The PKC family comprises 10 isozymes grouped into 3 classes: conventional (α, βI, βII, γ), novel (δ, ε, η/L, θ), and atypical (ζ, ι/λ) [1]
Using genetic and pharmacological approaches, we have shown PKCδ to play a negative role in regulating filopodia formation and platelet aggregation in response to collagen through a functional interaction with the actin regulatory protein VASP [15, 16]
Platelets play a central role in mediating atherothrombosis and are the target of numerous therapies aimed at reducing their activity, in the prevention of coronary artery thrombosis in heart attacks [45]
Summary
The PKC family comprises 10 isozymes grouped into 3 classes: conventional (α, βI, βII, γ), novel (δ, ε, η/L, θ), and atypical (ζ, ι/λ) [1]. It has been shown pharmacologically that PKC isoforms may exert a dual-control role in thrombus formation by mediating secretion and integrin activation under flow while suppressing phosphatidylserine exposure and subsequent thrombin generation and coagulation [7]. Using genetic and pharmacological approaches, we have shown PKCδ to play a negative role in regulating filopodia formation and platelet aggregation in response to collagen through a functional interaction with the actin regulatory protein VASP [15, 16]. PKCα has been identified as an essential factor in positively regulating α-granule and dense-granule secretion in platelets [17] as well as platelet aggregation [18]. We have recently shown, using biochemical and pharmacological approaches, that 2 tyrosine kinases, Syk and Src, physically and functionally interact with PKCα to regu-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
