Abstract
Oxidative stress-induced reactive oxygen species (ROS) are responsible for various neuronal diseases. Antioxidant 1 (Atox1) regulates copper homoeostasis and promotes cellular antioxidant defence against toxins generated by ROS. The roles of Atox1 protein in ischaemia, however, remain unclear. In this study, we generated a protein transduction domain fused Tat-Atox1 and examined the roles of Tat-Atox1 in oxidative stress-induced hippocampal HT-22 cell death and an ischaemic injury animal model. Tat-Atox1 effectively transduced into HT-22 cells and it protected cells against the effects of hydrogen peroxide (H2O2)-induced toxicity including increasing of ROS levels and DNA fragmentation. At the same time, Tat-Atox1 regulated cellular survival signalling such as p53, Bad/Bcl-2, Akt and mitogen-activate protein kinases (MAPKs). In the animal ischaemia model, transduced Tat-Atox1 protected against neuronal cell death in the hippocampal CA1 region. In addition, Tat-Atox1 significantly decreased the activation of astrocytes and microglia as well as lipid peroxidation in the CA1 region after ischaemic insult. Taken together, these results indicate that transduced Tat-Atox1 protects against oxidative stress-induced HT-22 cell death and against neuronal damage in animal ischaemia model. Therefore, we suggest that Tat-Atox1 has potential as a therapeutic agent for the treatment of oxidative stress-induced ischaemic damage.
Highlights
Human Antioxidant 1 (Atox1) genes were fused to a Tat peptide expression vector to produce cell-penetrating Tat-Atox1 proteins
Control Atox1 protein was manufactured in the absence of Tat Protein transduction domains (PTDs) (Fig. 1A)
Purified Tat-Atox1 proteins were identified by SDSPAGE and Western blotting
Summary
Antioxidant 1 (Atox1) protein, known as ATX1, consists of 68 amino acids and is a copper chaperone which plays a crucial a 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. The copper chaperone function of Atox is dependent on copper-binding residue in the N-terminal domain. Atox utilizes a copper-dependent transcription factor to increase promoter activity of cyclin D1 and SOD3, important regulators of cell cycle G1-S phase progression, which promote cell proliferation. The results of this study suggest that Atox is a therapeutic target for various diseases such as cardiovascular disease, cancer, and Wilson’s disease [1, 3, 9, 10]
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