Cellular adaptation mediated through Nrf2-induced glutamate cysteine ligase up-regulation against oxidative stress caused by iron overload in β-thalassemia/HbE patients

Abstract

Oxidative stress caused as a result of iron overload is implicated in clinical manifestation of beta-thalassemia/haemoglobin E (β-Thal/HbE). In this study, we investigated the cellular adaptation against oxidative stress in β-Thal/HbE patients. Twenty-four paediatric β-Thal/HbE patients and 22 healthy controls were recruited in the study. Blood samples from patients exhibited iron overload, elevation of lipid peroxidation, and marked diminution in the reduced glutathione (GSH) level. However, expression of glutamate-cysteine ligase catalytic (GCLC) subunit, a key enzyme in GSH biosynthesis, was up-regulated when compared with that in controls. GCLC protein levels were correlated with serum iron. There was an enhanced binding activity of the oligonucleotide probe for Nrf2-driven antioxidant response element (ARE) to nuclear protein from blood mononuclear cells of thalassemia subjects. In conclusion, β-Thal/HbE patients exhibit elevated plasma levels of GCLC expression and Nrf2-ARE binding activity, which may account for their adaptive survival response to oxidative stress.

Keywords:

• Adaptive response
• antioxidant response element
• glutamate cysteine ligase
• Nrf2
• β-thalassemia

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by grant-in-aids from National Research Council through Khon Kaen University and from Faculty of Medicine, Khon Kaen University, Thailand Research Fund and the Global Core Research Center (GCRC) grant [No. 2011 0030001] from the National Research Foundation (NRF), Republic of Korea.