PKCalpha regulates platelet granule secretion and thrombus formation in mice.
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.
Konopatskaya
Olga
O
Department of Physiology & Pharmacology, School of Medical Sciences, University of Bristol, Bristol, United Kingdom.
Gilio
Karen
K
Harper
Matthew T
MT
Zhao
Yan
Y
Cosemans
Judith M E M
JM
Karim
Zubair A
ZA
Whiteheart
Sidney W
SW
Molkentin
Jeffery D
JD
Verkade
Paul
P
Watson
Steve P
SP
Heemskerk
Johan W M
JW
Poole
Alastair W
AW
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D003594:Cytoplasmic Granules / Q000378:metabolism*; D016023:Integrins / Q000502:physiology; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D011493:Protein Kinase C / Q000502:physiology; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha / Q000502:physiology*; D015398:Signal Transduction; D013927:Thrombosis / Q000209:etiology*
D016023:Integrins; D000244:Adenosine Diphosphate; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha