Pioglitazone induces plasma platelet activating factor-acetylhydrolase and inhibits platelet activating factor-mediated cytoskeletal reorganization in macrophage

Abstract Platelet activating factor (PAF) is a key molecule for inflammation. To examine a role of peroxisome proliferator-activated receptor gamma (PPARγ) in inflammatory reactions of atherosclerosis, we investigated the effects of 15-deoxy- Δ12,14 -Prostaglandin J2 (15d-PGJ2) and pioglitazone, PPARγ ligands, on plasma PAF-acetylhydrolase (PAF-AH) expression in THP-1 macrophages. PAF-AH mRNA and protein were up-regulated by the PPARγ ligands. Prostaglandin F2α (PGF2α), a PARγ inhibitor, abrogated the up-regulation of PAF-AH mRNA by pioglitazone, suggesting that PPARγ activation is involved in the induction of PAF-AH by pioglitazone. As PAF promotes the cell motility with cytoskeletal reorganization, we investigated the effect of pioglitazone on PAF-mediated morphological changes in THP-1 macrophages. In the absence of pioglitazone, PAF promoted the elongation of actin cytoskeleton, which was inhibited by pretreatment with pioglitazone. In contrast, pioglitazone was not able to inhibit the morphological changes induced by C-PAF, a non-hydrolyzable PAF agonist. Thus, it is suggested that PAF-induced morphological changes could be inhibited by pioglitazone through PAF-AH, which rapidly hydrolyzed PAF. These data propose that PPARγ/PAF-AH pathway is a clinical target for the prevention against atherosclerosis.