Peroxisome proliferator-activated receptor γ and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles
Denise M. Ray*1, Sherry L. Spinelli*2, Stephen J. Pollock1, Thomas I. Murant1, Jamie J. O’Brien1, Neil Blumberg2, Charles W. Francis3, Mark B. Taubman4, Richard P. Phipps1
University of Rochester Medical Center, 1Environmental Medicine; 2Pathology and Laboratory Medicine; 3Medicine: Hematology-Oncology; 4Center for Cellular and Molecular Cardiology, Rochester, New York, USA
Platelets, microparticles, transcription factors, peroxisome proliferator-activated receptor γ (PPARγ), retinoic X receptor (RXR)
Peroxisome proliferator-activated receptor γ (PPARγ) and its ligands are important regulators of lipid metabolism, inflammation, and diabetes. We previously demonstrated that anucleate human platelets express the transcription factor PPARγ and that PPARγ ligands blunt platelet activation. To further understand the nature of PPARγ in platelets, we determined the platelet PPARγ isoform(s) and investigated the fate of PPARγ following platelet activation. Our studies demonstrated that human platelets contain only the PPARγ1 isoform and after activation with thrombin,TRAP,ADP or collagen PPARγ is released from internal stores. PPARγ release was blocked by a cytoskeleton inhibitor, Latrunculin A. Platelet-released PPARγ was complexed with the retinoid X receptor (RXR) and retained its ability to bind DNA. Interestingly, the released PPARγ and RXR were microparticle associated and the released PPARγ/RXR complex retained DNA-binding ability.Additionally, a monocytic cell line,THP-1, is capable of internalizing PMPs. Further investigation following treatment of these cells with the PPARγ agonist, rosiglitazone and PMPs revealed a possible transcellular mechanism to attenuate THP-1 activation. These new findings are the first to demonstrate transcription factor release from platelets, revealing the complex spectrum of proteins expressed and expelled from platelets,and suggests that platelet PPARγ has an undiscovered role in human biology.