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

Jingwei Liu, Qisong Xia, Qiuju Zhang, Hongwei Li, Jing Zhang, Ailing Li, Ruijuan Xiu
Shock 2009, 32 (3): 317-24
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.

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