title: Peroxisome proliferator-activated receptor-gamma ligands 15-deoxy-delta(12,14)-prostaglandin J2 and pioglitazone inhibit hydroxyl peroxide-induced TNF-alpha and lipopolysaccharide-induced CXC chemokine expression in neonatal rat cardiac myocytes.
abstract: Ligands for peroxisome proliferator-activated receptor gamma (PPAR-gamma) such as prostaglandin metabolite 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2) or thiazolidinedione pioglitazone have been identified as a new class of anti-inflammatory compounds with possible clinical applications. Reactive oxygen species play an important role in the generation of cellular damage by induction of proinflammatory cytokines and chemokines during myocardial I/R. These events were preceded by activation of the transcription factors nuclear factor (NF)-kappaB pathway. It has been suggested that myocardium overproduces TNF-alpha after I/R, and locally produced TNF-alpha is sufficient to cause severe impairment of cardiac function. LPS-induced CXC chemokine (LIX) is a rodent chemokine with potent neutrophil-chemotactic activity. Based on this concept, we examined the effects of 15d-PGJ2 and pioglitazone on oxidative stress-induced TNF-alpha and LIX expression in neonatal rat cardiac myocytes. Pretreatment of myocytes with 15d-PGJ2 or pioglitazone decreased hydrogen peroxide-induced TNF-alpha and LIX production (mRNA and protein) in a concentration-dependent manner. The beneficial effects of both ligands were associated with reduction of hydrogen peroxide-induced NF-kappaB activation. Treatment with 15d-PGJ2, but not pioglitazone, caused dose-dependent activation of heat shock factor 1, which could render cells unresponsive to stimulation of NF-kappaB. The cytoprotection afforded by pioglitazone was attenuated by the PPAR-gamma antagonist GW9662, which failed to affect the beneficial effects afforded by 15d-PGJ2. Taken together, these results demonstrate that treatment with these chemically distinct ligands of PPAR-gamma results in diverse anti-inflammatory mechanisms.
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. ljwgirl361@163.com
authors.forename: Jingwei
authors.initials: J
authors.lastname: Liu
authors.forename: Qisong
authors.initials: Q
authors.lastname: Xia
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Ailing
authors.initials: A
authors.lastname: Li
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Xiu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D019743:Chemokines, CXC; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D015230:Prostaglandin D2; D000077205:Pioglitazone