Pioglitazone induces plasma platelet activating factor-acetylhydrolase and inhibits platelet activating factor-mediated cytoskeletal reorganization in macrophage.
Platelet activating factor (PAF) is a key molecule for inflammation. To examine a role of peroxisome proliferator-activated receptor gamma (PPARgamma) in inflammatory reactions of atherosclerosis, we investigated the effects of 15-deoxy-(Delta12,14)-Prostaglandin J2 (15d-PGJ2) and pioglitazone, PPARgamma ligands, on plasma PAF-acetylhydrolase (PAF-AH) expression in THP-1 macrophages. PAF-AH mRNA and protein were up-regulated by the PPARgamma ligands. Prostaglandin F2alpha (PGF2alpha), a PARgamma inhibitor, abrogated the up-regulation of PAF-AH mRNA by pioglitazone, suggesting that PPARgamma 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 PPARgamma/PAF-AH pathway is a clinical target for the prevention against atherosclerosis.
Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
Chinuyo
C
Sumita
Makiko
M
Maeda
Yasushi
Y
Fujio
Jooyeon
J
Kim
Junko
J
Fujitsu
Soji
S
Kasayama
Isamu
I
Yamamoto
Junichi
J
Azuma
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism*; D015237:Dinoprost / Q000502:physiology; D004790:Enzyme Induction; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000077205:Pioglitazone; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000502:physiology
D010972:Platelet Activating Factor; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D015237:Dinoprost; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000077205:Pioglitazone