DJ-1 upregulates anti-oxidant enzymes and attenuates hypoxia/re-oxygenation-induced oxidative stress by activation of the nuclear factor erythroid 2-like 2 signaling pathway

Abstract

Abstract. DJ-1 protein, as a multifunctional intracellular protein, has an important role in transcriptional regulation and anti-oxidant stress. A recent study by our group showed that DJ-1 can regulate the expression of certain anti-oxidant enzymes and attenuate hypoxia/re-oxygenation (H/R)-induced oxidative stress in the cardiomyocyte cell line H9c2; however, the detailed molecular mechanisms have remained to be elucidated. Nuclear factor erythroid 2-like 2 (Nrf2) is an essential transcription factor that regulates the expression of several anti-oxidant genes via binding to the anti-oxidant response element (ARE). The present study investigated whether activation of the Nrf2 pathway is responsible for the induction of anti-oxidative enzymes by DJ-1 and contributes to the protective functions of DJ-1 against H/R-induced oxidative stress in H9c2 cells. The results demonstrated that DJ-1-overexpressing H9c2 cells exhibited anti-oxidant enzymes, including manganese superoxide dismutase, catalase and glutathione peroxidase, to a greater extent and were more resistant to H/R-induced oxidative stress compared with native cells, whereas DJ-1 knockdown suppressed the induction of these enzymes and further augmented the oxidative stress injury. Determination of the importance of Nrf2 in DJ-1-mediated anti-oxidant enzymes induction and cytoprotection against oxidative stress induced by H/R showed that overexpression of DJ-1 promoted the dissociation of Nrf2 from its cytoplasmic inhibitor Keap1, resulting in enhanced levels of nuclear translocation, ARE-binding and transcriptional activity of Nrf2. Of note, Nrf2 knockdown abolished the DJ-1-mediated induction of anti-oxidant enzymes and cytoprotection against oxidative stress induced by H/R. In conclusion, these findings indicated that activation of the Nrf2 pathway is a critical mechanism by which DJ-1 upregulates anti-oxidative enzymes and attenuates H/R-induced oxidative stress in H9c2 cells. IntroductionOxidative stress is known to have an important role in the pathogenesis of certain cardiovascular diseases, including atherosclerosis, myocardial ischemia-reperfusion injury and chronic heart failure (1). Endogenous anti-oxidant systems include a number of proteins or enzymes, e.g., superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as non-enzymatic, low-molecular-weight anti-oxidant compounds, including glutathione and ascorbic acid, which constitute the first line of defence against oxidative stress and maintain the redox environment of the body (2). Mounting evidence indicates that stimulation of endogenous anti-oxidant systems is an important strategy for achieving cardioprotection against ischemia-reperfusion injury, and is also one of essential mechanisms of anti-oxidative stress effect of certain proteins (3,4).DJ-1, a ubiquitously expressed and highly conserved intracellular protein, was originally discovered in 1997 as a novel oncogene product that can transform mouse NIH3T3 cells in combination with H-Ras or c-Myc (5). Subseq...

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