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 f ibrosis associated with chronic liver diseases. Apoptosis of these cells is emerging as a key process in the resolution of liver fibrosis. Here, we ex amined the effects of cyclopentenone prostaglandins on apoptosis of human h MFs. Cyclopentenone prostaglandins of the J series markedly reduced hMF via bility, with 15-deoxy-Delta (12,14)-prostaglandin J2 (15-d-PGJ(2)) being th e most potent. This effect was independent of peroxisome-proliferator-activ ated receptors (PPARs), because PPAR gamma and PPAR alpha agonists did not affect hMF cell viability, and PPAR-gamma, the nuclear receptor for 15-d-PG J(2), was not expressed in hMFs. Moreover, 15-d-PGJ(2) did not act via a ce ll surface G protein-coupled receptor, as shown in guanosine-5'-O-(3-thiotr iphosphate) binding assays. Cell death resulted from an apoptotic process, because 15-d-PGJ(2)-treated hMFs exhibited condensed nuclei, fragmented DNA , and elevated caspase-3 activity. Moreover, the caspase inhibitor Z-Val-Al a-Asp (OCH3)-fluoromethyl ketone blocked the cytotoxic effect of 15-d-PGJ(2 ). The apoptotic effects of 15-d-PGJ2 were reproduced by H2O2 and blocked b y the antioxidants N-acetylcysteine (NAC), N-(2-mercapto-propionyl)-glycine (NMPG) and pyrrolidine dithiocarbamate (PDTC). Accordingly, 15-d-PGJ(2) ge nerated rapid production of reactive oxygen species in hMFs, via a NAC/NMPG /PDTC-sensitive pathway. In conclusion, 15-d-PGJ(2) induces apoptosis of hu man hMFs via a novel mechanism involving oxidative stress and unrelated to activation of its nuclear receptor PPAR gamma. These data underline the ant ifibrogenic potential of 15-d-PGJ(2).