15-Deoxy-Delta12,14-prostaglandin J(2) protects against nitrosative PC12 cell death through up-regulation of intracellular glutathione synthesis.
Nitrosative stress with subsequent inflammatory cell death has been associated with many neurodegenerative disorders. Expression of inducible nitric-oxide synthase and production of nitric oxide (NO) have been frequently elevated in many inflammatory disorders. NO can rapidly react with superoxide anion, producing more reactive peroxynitrite. In the present study, exposure of rat pheochromocytoma (PC12) cells to the peroxynitrite donor 3-morpholinosydnonimine hydrochloride (SIN-1) induced apoptosis, which accompanied depletion of intracellular glutathione (GSH), c-Jun N-terminal kinase activation, mitochondrial membrane depolarization, the cleavage of poly(ADP-ribose)polymerase, and DNA fragmentation. During SIN-1-induced apoptotic cell death, expression of inducible cyclooxygenase (COX-2), and peroxisome proliferator-activated receptor-gamma (PPARgamma) was elevated. SIN-1 treatment resulted in elevated production of 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenous PPARgamma activator. Preincubation with 15d-PGJ(2) rendered PC12 cells resistant to nitrosative stress induced by SIN-1. 15d-PGJ(2) fortified an intracellular GSH pool through up-regulation of glutamylcysteine ligase, thereby preventing cells from SIN-1-induced GSH depletion. The above findings suggest that 15d-PGJ(2) may act as a survival mediator capable of augmenting cellular thiol antioxidant capacity through up-regulation of the intracellular GSH synthesis in response to the nitrosative insult.
Lim
So-Young
SY
College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Jang
Jung-Hee
JH
Na
Hye-Kyung
HK
Lu
Shelly C
SC
Rahman
Irfan
I
Surh
Young-Joon
YJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000502:physiology; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000096:biosynthesis*; D007527:Isoenzymes / Q000502:physiology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D047495:PPAR gamma / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D051381:Rats; D015534:Trans-Activators / Q000502:physiology; D015854:Up-Regulation
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D047495:PPAR gamma; D015534:Trans-Activators; C002385:linsidomine; D008981:Molsidomine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D015230:Prostaglandin D2