PB0397 - PPAR-alpha inhibition of platelet activation and thrombosis

Background: Eicosanoids were recently shown to regulate platelets through activation of peroxisome proliferator-activated receptors (PPARs). There exists a significant gap in our knowledge of how a transcription regulator such as PPAR can regulate activity in the platelet . Importantly, determining the underlying mechanism by which PPAR limits platelet activation in a non-genomic manner represents a significant gap in our understanding of how fatty acids modulate platelet function to decrease the risk of a thrombotic event.

Aims: To delineate the mechanisms by which eicosanoid activation of PPAR-alpha attenuates platelet activation and clot formation.

Methods: co-IP experiments were conducted to determine the protein complex interactions of PPAR with other proteins and signaling pathways in the platelet. Additionally, we have assessed PKC activation and calcium mobilization and investigated the signaling correlates in platelet activity including small G protein Rap1, integrin GPIIb/IIIa, and platelet aggregation. Finally, we evaluated the role of PPAR in regulating thrombosis in vivo in the mouse.

Results: PKC activation and calcium mobilization were found to be dependent on PPAR activation. Rap1-GTP binding was decreased following PPAR activation and aggregation, granule secretion, and integrin activation was all attenuated in PPAR activated condition, but were rescued when PPAR activity was blocked. Finally, the extent of clot formation was significantly decreased with PPAR activation and was reversed in animals lacking PPAR.

Conclusion(s): this study defined PPAR as an important signaling protein regulating the extent of platelet activity ex vivo as well as the ability to form a clot in vivo. These studies help to determine that PPAR-alpha activation represents a novel method for limiting platelet activation and thrombosis and this PPAR may represent a new target for directed antiplatelet therapy.