PPARbeta/delta agonists modulate platelet function via a mechanism involving PPAR receptors and specific association/repression of PKCalpha--brief report.
OBJECTIVE
Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a nuclear receptor found in platelets. PPARbeta/delta agonists acutely inhibit platelet function within a few minutes of addition. As platelets are anucleated, the effects of PPARbeta/delta agonists on platelets must be nongenomic. Currently, the particular role of PPARbeta/delta receptors and their intracellular signaling pathways in platelets are not known.


RESULTS
We have used mice lacking PPARbeta/delta (PPARbeta/delta(-/-)) to show the effects of the PPARbeta/delta agonist GW501516 on platelet adhesion and cAMP levels are mediated specifically by PPARbeta/delta, however GW501516 had no PPARbeta/delta-specific effect on platelet aggregation. Studies in human platelets showed that PKCalpha, which can mediate platelet activation, was bound and repressed by PPARbeta/delta after platelets were treated with GW501516.


CONCLUSIONS
These data provide evidence of a novel mechanism by which PPAR receptors influence platelet activity and thereby thrombotic risk.
Ali
Ferhana Y
FY
Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, London, UK.
Hall
Matthew G
MG
Desvergne
Béatrice
B
Warner
Timothy D
TD
Mitchell
Jane A
JA
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism*; D048068:PPAR-beta / Q000819:agonists* / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011336:Probability; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology*
C425931:GW 501516; D047494:PPAR delta; D048068:PPAR-beta; D010975:Platelet Aggregation Inhibitors; D013844:Thiazoles