15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors.
Hepatic myofibroblasts (hMFs) play a key role in the development of liver fibrosis associated with chronic liver diseases. Apoptosis of these cells is emerging as a key process in the resolution of liver fibrosis. Here, we examined the effects of cyclopentenone prostaglandins on apoptosis of human hMFs. Cyclopentenone prostaglandins of the J series markedly reduced hMF viability, with 15-deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) being the most potent. This effect was independent of peroxisome-proliferator-activated receptors (PPARs), because PPARgamma and PPARalpha agonists did not affect hMF cell viability, and PPARgamma, the nuclear receptor for 15-d-PGJ2, was not expressed in hMFs. Moreover, 15-d-PGJ2 did not act via a cell surface G protein-coupled receptor, as shown in guanosine-5'-O-(3-thiotriphosphate) binding assays. Cell death resulted from an apoptotic process, because 15-d-PGJ2-treated hMFs exhibited condensed nuclei, fragmented DNA, and elevated caspase-3 activity. Moreover, the caspase inhibitor Z-Val-Ala-Asp(OCH3)-fluoromethyl ketone blocked the cytotoxic effect of 15-d-PGJ2. The apoptotic effects of 15-d-PGJ2 were reproduced by H2O2 and blocked by the antioxidants N-acetylcysteine (NAC), N-(2-mercapto-propionyl)-glycine (NMPG) and pyrrolidine dithiocarbamate (PDTC). Accordingly, 15-d-PGJ2 generated rapid production of reactive oxygen species in hMFs, via a NAC/NMPG/PDTC-sensitive pathway. In conclusion, 15-d-PGJ2 induces apoptosis of human hMFs via a novel mechanism involving oxidative stress and unrelated to activation of its nuclear receptor PPARgamma. These data underline the antifibrogenic potential of 15-d-PGJ2.
Li
L
L
Unité INSERM 99, Hôpital Henri Mondor, 94010 Créteil, France.
Tao
J
J
Davaille
J
J
Feral
C
C
Mallat
A
A
Rieusset
J
J
Vidal
H
H
Lotersztajn
S
S
D017209:Apoptosis / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology*; D018384:Oxidative Stress; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000502:physiology*; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019204:GTP-Binding Proteins; D015230:Prostaglandin D2