Effects of Peroxisome Proliferator-Activated Receptor Ligand and Brown Seaweed Based Compound on Megakaryocyte

Abstract

Platelets are anuclear cells released from megakaryocytes, the rare myeloid cells that undergo multiple rounds of endomitosis before releasing platelets. Platelets, known as the mediator of thrombosis, are emerging as cellular mediators of type II diabetes, atherosclerosis, cancer cell metastasis, and immune responses. Despite the lack of a nucleus, they express a large number of transcription factors including peroxisome proliferator-activated receptor (PPAR). PPAR needs ligand-binding to be activated. PPAR, a ligand-activated transcription factor, consists of 3 isoforms: α, β/δ, γ, and requires heterodimerization with retinoid X receptor to modulate transcription of target genes. PPARγ is involved in glucose metabolism, inflammation, and differentiation and functions of adipose tissue. Recent studies have reported that the PPARγ inhibits platelet activation and aggregation. Also, studies have reported the PPARγ and ligand of PPARγ as the factor influences the hematopoietic system. They could affect the roles of erythroid, myeloid, monocytic, and lymphocytic cell function during an immune response, and modulate proliferation and maturation of erythroid progenitor cells. The endogenous 15-deoxy-Δ prostaglandin J2 (15d-PGJ2) is a ligand of PPARγ. Biologically, 15d-PGJ2 is the most active metabolite of prostaglandin D2. Fucoidans, fucose-containing sulfated polysaccharides, are constituents of brown seaweed and some marine invertebrates. Extensive studies have reported their various biological effects including immunostimulation, anti-tumor, antiviral, antithrombotic and anticoagulant activities. By far the anticoagulant and antithrombotic actions of fucoidans are the most widely recognized bioactivities, but the basis for these activities is not completely understood. We are interested in the influences of 15d-PGJ2 and fucoidans to the megakaryocytic differentiation and the platelet production, as well as the influences of 15d-PGJ2 and fucoidans to the thrombosis and coagulation system. Due to their antithrombotic and anticoagulant activities, they have the probability of the application as the novel therapeutic agents to cardiovascular disease. Also, if they have the abilities inducing the production of platelet, they could be the stable solution of platelet supply to the thrombocytopenic patients. In this study, we evaluated the effects of 15d-PGJ2 and fucoidans on megakaryocytes and platelets with diverse methods from protein to the molecular level. This study aims to determine 1) whether the 15d-PGJ2 and fucoidans encourage the megakaryocytes to produce platelets actively; 2) whether the 15d-PGJ2 and fucoidans possess the anticoagulant and antithrombotic actions, and 3) whether specific factors, such as prostaglandins or genes, explain the mechanism of how the 15d-PGJ2 and fucoidans influence differentiation and function of the platelets. To search these factors, we also included PPARα, which activates fatty acid catabolism and stimulates gluconeogenesis, attenuates inflammatory responses, and participates in the amino acid metabolism, and COX-2, which is responsible for the formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. Original Article