Human bone marrow megakaryocytes and platelets express PPARgamma, and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor important in lipid metabolism, diabetes, and inflammation. We evaluated whether human platelets and megakaryocytes express PPARgamma and whether PPARgamma agonists influence platelet release of bioactive mediators. Although PPARgamma is mainly considered a nuclear receptor, we show that enucleate platelets highly express PPARgamma protein as shown by Western blotting, flow cytometry, and immunocytochemistry. Meg-01 megakaryocyte cells and human bone marrow megakaryocytes also express PPARgamma. Platelet and Meg-01 PPARgamma bound the PPARgamma DNA consensus sequence, and this was enhanced by PPARgamma agonists. Platelets are essential not only for clotting, but have an emerging role in inflammation in part due to their release or production of the proinflammatory and proatherogenic mediators CD40 ligand (CD40L) and thromboxanes (TXs). Platelet incubation with a natural PPARgamma agonist, 15d-PGJ(2), or with a potent synthetic PPARgamma ligand, rosiglitazone, prevented thrombin-induced CD40L surface expression and release of CD40L and thromboxane B(2) (TXB(2)). 15d-PGJ(2) also inhibited platelet aggregation and adenosine triphosphate (ATP) release. Our results show that human platelets express PPARgamma and that PPARgamma agonists such as the thiazolidinedione class of antidiabetic drugs have a new target cell, the platelet. This may represent a novel mechanism for treatment of inflammation, thrombosis, and vascular disease in high-risk patients.
Akbiyik
Filiz
F
Box 850, Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Rochester, NY 14642, USA.
Ray
Denise M
DM
Gettings
Kelly F
KF
Blumberg
Neil
N
Francis
Charles W
CW
Phipps
Richard P
RP
D000255:Adenosine Triphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000502:physiology*; D001854:Bone Marrow Cells / Q000502:physiology; D023201:CD40 Ligand / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008533:Megakaryocytes / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D023201:CD40 Ligand; D013929:Thromboxane B2; D000255:Adenosine Triphosphate; D015230:Prostaglandin D2