Abstract 5888: Activation of Peroxisome Proliferator-activated Receptor α in Megakaryocytes Reduces the Expression of Platelet-drived Growth Factor-BB in Platelets
Background: Platelet-derived growth factor (PDGF)-BB released from activated platelets at sites of injured vascular endothelium caused the proliferation and migration of vascular smooth muscle cells (VSMC), leading to vascular remodeling. Activation of peroxisome proliferator-activated receptor (PPAR)α in endothelial cells or VSMC elicits anti-inflammatory and anti-thrombotic actions. The objective of this study was to investigate the effects of PPARα activators on PDGF-BB expression in megakaryocytes/platelets.
Methods and Results: The expressions of PPARα mRNA and protein in a human erythroleukemia (HEL) cells were clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy, respectively. Treatment with phorbol 12-myristate 13 acetate (TPA) markedly enhanced the expression of mature megakaryocyte/platelet-specific surface marker, CD41 and CD42b in HEL cells, indicating differentiation into megakaryocytic cells. But, the expression level of PPARα was unchanged regardless of TPA treatment. Both PDGF-B mRNA level determined by quantitative real time-PCR and PDGF-BB protein level in culture media determined by ELISA were markedly increased by TPA treatment in HEL cells. The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein were significantly decreased by the treatment with PPARα activators, Wy14643 and Fenofibric acid, in a dose-dependent manner. Inflammatory Cytokines, such as interleukin (IL)-1β or IL-6, -induced PDGF-BB expression was significantly suppressed by the treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/ 105 platelets (mean± SD, p<0.05) by the treatment with 300mg of fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia.
Conclusions: Activation of PPAR α in megakaryocytes reduces PDGF-BB expression in plateles. PPARα activators including fenofibric acid may exert vasculo-protective action through suppression of PDGF-BB production in megakaryocytes/platelets pathway.