L71	Influences of nuclear receptors on platelet function.
1T.Warner, 1F.Ali, 1D.Bishop-Bailey, 2J.Mitchell, 1L.Moraes
1William Harvey Research Institute, Barts & the London, Queen Mary's School of Medicine & Dentistry, London, GB; 2Cardiothoracic Pharmacology, Unit of Critical Care, National Heart & Lung Institute, Imperial College, London, GB.

Nuclear receptors, such as peroxisome proliferator activator receptors (PPARs) and retinoid X receptors (RXRs), regulate multiple signalling pathways and activate transcription, often as heterodimeric partners of other nuclear receptors. However, emerging experimental data suggest that nuclear receptors might also exert influences through non-nuclear pathways. Platelets do not contain nuclei and provide an experimental system in which to explore such non-nuclear pathways of nuclear receptor function. Our studies have employed whole human blood, platelet rich human plasma, washed human platelets and the megakaryoblast cell line Meg-01. The presence of nuclear receptor isoforms was determined by Western blotting and platelet activation measured by aggregation in whole blood and washed platelets using electrical impedance and light transmission aggregometry, respectively. Platelets and Meg 01 cells expressed both PPAR and RXR isoforms. For example, the PPAR-delta ligand, GW0742, inhibited aggregation in both whole blood and platelet rich plasma in a concentration-dependent manner, e.g. 40μM inhibited ADP-induced aggregation by 70%, and synergised with the NO donor sodium nitroprusside. Similarly, U46619-induced platelet aggregation was inhibited by the RXR ligand 9 cis-retinoic acid (1-20μM). The effects of 9 cis-retinoic acid were associated with inhibition of receptor coupled Gq-dependant Rac activation. In summary, human platelets express PPAR and RXR isoforms and selective ligands inhibit aggregation. In the case of RXR these effects may be linked to influences on Gq signaling. These results highlight novel mechanisms for rapid and functional non-genomic signaling of nuclear receptors. This work was funded by the Research Advisory Board of St Bartholomews and the Royal London and the British Heart Foundation.

Copyright © 2005 S. Karger AG, Basel. Any further use of this abstract requires written permission from the publisher.