Platelets as a Novel Target for PPAR?? Ligands

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is an important transcription factor for lipid and glucose metabolism. Currently, the PPARgamma ligands rosiglitazone and pioglitazone are used for the treatment of type 2 diabetes mellitus because they are potent insulin sensitizers. Recently, PPARgamma 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 PPARgamma and that PPARgamma ligands, both natural and synthetic, inhibit platelet activation and release of bioactive mediators. In particular, release of soluble CD40 ligand (sCD40L) and thromboxane (TXA(2)) was inhibited by PPARgamma 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 PPARgamma will, therefore, be an important treatment strategy for the attenuation of chronic inflammatory processes and prevention of thrombus formation.

Relationship between Platelet PPARs, cAMP Levels, and P-Selectin Expression: Antiplatelet Activity of Natural Products

“…PPARs are expressed in human platelets [37]. In this context, PPARs appear to play a major role in the regulation of atherogenesis by countering the inflammation-provoking action of platelet adhesion and activation [38]. The antiplatelet activity of statins and fibrates on platelet function is mediated by PPARs activation via a novel mechanism that involves the inhibition of protein kinase- α (PKC- α ) [39].…”

Regulation of Lymphocyte Function by PPARγ: Relevance to Thyroid Eye Disease‐Related Inflammation

“…Three isoforms of PPAR γ , PPAR γ 1, PPAR γ 2, and PPAR γ 3 are generated by alternative splicing of the same mRNA [3]. PPARs are differentially expressed in a variety of tissues and are important to the regulation of lipid and carbohydrate metabolism, energy homeostasis, cellular differentiation, apoptosis, and immunity and inflammatory responses [2, 4–6].…”

“…PPARs are differentially expressed in a variety of tissues and are important to the regulation of lipid and carbohydrate metabolism, energy homeostasis, cellular differentiation, apoptosis, and immunity and inflammatory responses [2, 4–6]. The physiological functions of PPAR α and PPAR γ have been well characterized, whereas the physiological function of PPAR β / δ is poorly understood although the protein is widely distributed [3]. PPAR α is expressed in brown adipose tissue, liver, kidney, heart, and skeletal muscle, but is also detected in cells of the vasculature and the immune system [1, 3, 7–10].…”

“…The physiological functions of PPAR α and PPAR γ have been well characterized, whereas the physiological function of PPAR β / δ is poorly understood although the protein is widely distributed [3]. PPAR α is expressed in brown adipose tissue, liver, kidney, heart, and skeletal muscle, but is also detected in cells of the vasculature and the immune system [1, 3, 7–10]. Its activation affects transcriptional expression of many genes involved in fatty acid oxidation, lipid metabolism, and inflammation [8, 11].…”

“…PPAR γ is highly expressed in adipose tissue, colon, retina, and in cells of the immune system, including platelets [1, 3–5, 19–25]. The PPAR γ 1 isoform is the more widely expressed, while PPAR γ 2 is mainly found in adipose tissue and liver [3, 26].…”