Peroxisome proliferator-activated receptor gamma and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles.
Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands are important regulators of lipid metabolism, inflammation, and diabetes. We previously demonstrated that anucleate human platelets express the transcription factor PPARgamma and that PPARgamma ligands blunt platelet activation. To further understand the nature of PPARgamma in platelets, we determined the platelet PPARgamma isoform(s) and investigated the fate of PPARgamma following platelet activation. Our studies demonstrated that human platelets contain only the PPARgamma1 isoform and after activation with thrombin, TRAP, ADP or collagen PPARgamma is released from internal stores. PPARgamma release was blocked by a cytoskeleton inhibitor, Latrunculin A. Platelet-released PPARgamma was complexed with the retinoid X receptor (RXR) and retained its ability to bind DNA. Interestingly, the released PPARgamma and RXR were microparticle associated and the released PPARgamma/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 PPARgamma 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 PPARgamma has an undiscovered role in human biology.
Ray
Denise M
DM
University of Rochester Medical Center, Environmental Medicine, Rochester, New York 14642, USA .
Spinelli
Sherry L
SL
Pollock
Stephen J
SJ
Murant
Thomas I
TI
O'Brien
Jamie J
JJ
Blumberg
Neil
N
Francis
Charles W
CW
Taubman
Mark B
MB
Phipps
Richard P
RP
D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D005260:Female; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D015539:Platelet Activation; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D049230:Retinoid X Receptor beta / Q000378:metabolism; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D053778:Thiazolidines / Q000494:pharmacology; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D022161:Transport Vesicles / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D047495:PPAR gamma; D010446:Peptide Fragments; D020033:Protein Isoforms; D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D053778:Thiazolidines; C082835:thrombin receptor peptide (42-47); D000077154:Rosiglitazone; D003094:Collagen; D004247:DNA; D013917:Thrombin; C037067:latrunculin A