HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Human bone marrow megakaryocytes and platelets express PPAR , and PPAR agonists blunt platelet release of CD40 ligand and thromboxanes

Peroxisome proliferator-activated receptor (PPAR ) is a ligand-activated transcription factor important in lipid metabolism, diabetes, and inflammation. We evaluated whether human platelets and megakaryocytes express PPAR and whether PPAR agonists influence platelet release of bioactive mediators. Although PPAR is mainly considered a nuclear receptor, we show that enucleate platelets highly express PPAR protein as shown by Western blotting, flow cytometry, and immunocytochemistry. Meg-01 megakaryocyte cells and human bone marrow megakaryocytes also express PPAR . Platelet and Meg-01 PPAR bound the PPAR DNA consensus sequence, and this was enhanced by PPAR 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 PPAR agonist, 15d-PGJ2, or with a potent synthetic PPAR ligand, rosiglitazone, prevented thrombin-induced CD40L surface expression and release of CD40L and thromboxane B2 (TXB2). 15d-PGJ2 also inhibited platelet aggregation and adenosine triphosphate (ATP) release. Our results show that human platelets express PPAR and that PPAR 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. (Blood. 2004;104:1361-1368)