Role of nuclear receptor signaling in platelets: antithrombotic effects of PPARbeta.
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate at the transcriptional level the function of many target genes. Three PPARs are known: alpha, beta (sometimes called delta), and gamma. The better studied are PPARalpha and PPARgamma, which are activated by fibrates and thiazolidinediones/glitazones, respectively. It is now believed that activation of the PPARs could be associated with the prevention of heart attack and stroke in humans. Here we report, for the first time, that human platelets contain PPARbeta and that its selective activation inhibits platelet aggregation. PPARbeta is a putative receptor for prostacyclin. Prostacyclin is an important antithrombotic hormone that synergizes with nitric oxide to inhibit platelet aggregation. In the current study, we show that PPARbeta ligands similarly synergize with nitric oxide to inhibit platelet aggregation. These observations challenge our view of a nuclear receptor because PPARbeta is present and active in nonnucleated platelets. Furthermore, these data suggest that some of the antithrombotic actions of prostacyclin may be mediated via activation of PPARs. Thus, our results identify PPARbeta as a novel antiplatelet target that may mediate some of the effects of prostacyclin in blood.
Ali
Ferhana Y
FY
Unit of Critical Care Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, UK.
Davidson
Simon J
SJ
Moraes
Leonardo A
LA
Traves
Suzanne L
SL
Paul-Clark
Mark
M
Bishop-Bailey
David
D
Warner
Timothy D
TD
Mitchell
Jane A
JA
D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
D048068:PPAR-beta; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D002118:Calcium