Platelets as a Novel Target for PPARγ LigandsImplications for Inflammation, Diabetes, and Cardiovascular Disease

Peroxisome proliferator-activated receptor γ (PPARγ) is an important transcription factor for lipid and glucose metabolism. Currently, the PPARγ ligands rosiglitazone and pioglitazone are used for the treatment of type 2 diabetes mellitus because they are potent insulin sensitizers. Recently, PPARγ has emerged as an important anti-inflammatory factor. Platelets, anucleate cells involved in hemostasis, have also been implicated as key contributors to inflammation, because they produce many pro-inflammatory and pro-atherogenic mediators when activated. Surprisingly, it was discovered recently that platelets contain PPARγ and that PPARγ ligands, both natural and synthetic, inhibit platelet activation and release of bioactive mediators. In particular, release of soluble CD40 ligand (sCD40L) and thromboxane (TXA2) was inhibited by PPARγ ligands in thrombin-activated platelets. CD40L signaling induces pro-inflammatory processes in many cell types, and increased blood levels of sCD40L are closely associated with inflammation, diabetes, and cardiovascular disease. Targeting platelet PPARγ will, therefore, be an important treatment strategy for the attenuation of chronic inflammatory processes and prevention of thrombus formation.