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Qingjun Zhou, Lingling Yang, Mingli Qu; Trichostatin A inihibits TGF-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5249.
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© ARVO (1962-2015); The Authors (2016-present)
Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on TGF-β-induced myofibroblast differentiation of corneal fibroblasts in vitro.
Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation and collagen gel contraction. ROS, H2O2, intracellular glutathione (GSH) level, cellular total antioxidant capacity and the activation of Nrf2-ARE signaling were determined with various assays.
Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H2O2 accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation.
This study provides the first evidence implicating that TSA inihibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling.
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