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. 2007;12(1):101-6.
doi: 10.1179/135100007X162266.

Submicromolar concentrations of 4-hydroxynonenal induce glutamate cysteine ligase expression in HBE1 cells

Hongqiao Zhang  1 , Nathalie Court, Henry Jay Forman
Affiliations

Submicromolar concentrations of 4-hydroxynonenal induce glutamate cysteine ligase expression in HBE1 cells

Hongqiao Zhang et al. Redox Rep. 2007.

VSports - Abstract

4-Hydroxynonenal (HNE), a major electrophilic product of lipid peroxidation, is regarded as both a marker of oxidative stress and a mediator of oxidative damage. At subtoxic concentrations, however, this compound has been shown to be a signalling molecule that can induce the expression of various antioxidant/detoxification enzymes, including glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the de novo synthesis of glutathione. GCL consists of a catalytic (GCLC) and modulatory (GCLM) subunit, which are encoded by separate genes VSports手机版. Here, we investigated the effect of submicromolar concentrations of HNE on the expression of the GCL genes and the transcription factors involved. We demonstrated that submicromolar concentrations of HNE (as little as 0. 3 muM) could increase the expression of both GCLC and GCLM. We also found that the induction of GCL expression was abrogated by siRNA for Nrf2. Our data suggest that a submicromolar concentration of HNE, as found in human plasma under physiological conditions, can induce GCL transcription in cultured cells implying that 'basal' expression of GCL is under regulation by lipid peroxidation that occurs under physiological conditions. Moreover, this induction is mediated through the EpRE-Nrf2 signalling pathway thought to be predominantly active only during stress. .

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VSports手机版 - Figures

Fig. 1
Fig. 1
Submicromolar concentrations of HNE induce GCL gene expression.(A) mRNA levels of GCLC and GCLM after exposure to HNE. HBE1 cells were exposed to HNE or vehicle alone at the doses indicated every 3 h for 9 h and then harvested at 12 h. GCLC and GCLM mRNA levels were measured with real-time PCR method. n = 4, *P < 0.05.
Fig. 2
Fig. 2
Effects of HNE on activity of GCL promoters. HBE1 cells were transfected with plasmids −3802/GCLC 5′-luc and −1927/GCLM 5′-luc and 24 h after transfection, cells were treated as described above. Luciferase activity was normalized with the activity of co-transfected β-galactosidase. n = 3, *P < 0.05.
Fig. 3
Fig. 3
Nrf2 protein in the cytosol (A) and nucleus (B) after siRNA treatment. HBE1 cells were transfected with 50 nM siRNA specific for human Nrf2 mRNA (siRNA-Nrf2) or 50 nM siRNA that does not target any known cellular mRNA (siRNA-control) for 24 h before treatment with 10 µM HNE for 1 h as described in Materials and Methods. The cytosol and nuclear proteins were then extracted and Western blotting was performed.
Fig. 4
Fig. 4
Effects of Nrf2 silencing on HNE-mediated GCL induction. (A) Effect on GCLC induction. (B) Effect on GCLM induction. HBE1 cells were transfected with plasmids −3802/GCLC 5′-luc or −1927/GCLM 5′-luc and 50 nM siRNA-Nrf2 or siRNA-control. Twenty-four hours after transfection, cells were treated with 1 µM HNE every 3 h for 12 h and the luciferase activity was determined. n = 3, *P < 0.05 compared with siRNA-control without HNE treatment, and #P < 0.05, compared with siRNA-control with HNE treatment.
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