DJ-1 Mediates the Delayed Cardioprotection of Hypoxic Preconditioning Through Activation of Nrf2 and Subsequent Upregulation of Antioxidative Enzymes

Abstract

We have recently shown that DJ-1 is implicated in the delayed cardioprotective effect of hypoxic preconditioning (HPC) against hypoxia/reoxygenation (H/R) injury as an endogenous protective protein. This study aims to further investigate the underlying mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress. Using a well-characterized cellular model of HPC from rat heart-derived H9c2 cells, we found that HPC promoted nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein-1 (Keap1) dissociation and resulted in increased nuclear translocation, antioxidant response element-binding, and transcriptional activity of Nrf2 24 hours after HPC, with subsequent upregulation of manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1), which provided delayed protection against H/R-induced oxidative stress in normal H9c2 cells. However, the aforementioned effects of HPC were abolished in DJ-1-knockdown H9c2 cells, which were restored by restoration of DJ-1 expression. Importantly, we showed that inhibition of the Nrf2 pathway in H9c2 cells mimicked the effects of DJ-1 knockdown and abolished HPC-derived induction of antioxidative enzymes (MnSOD and HO-1) and the delayed cardioprotection. In addition, inhibition of Nrf2 also reversed the effects of restored DJ-1 expression on induction of antioxidative enzymes and delayed cardioprotection by HPC in DJ-1-knockdown H9c2 cells. Taken together, this work revealed that activation of Nrf2 pathway and subsequent upregulation of antioxidative enzymes could be a critical mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress in H9c2 cells.

DJ‐1 plays an obligatory role in the cardioprotection of delayed hypoxic preconditioning against hypoxia/reoxygenation‐induced oxidative stress through maintaining mitochondrial complex I activity

“…DJ‐1 is known to be present in the heart and only recently has its cardioprotective role in myocardial I/R injury been uncovered through a DJ‐1‐antioxidative stress pathway . Notably, the important role of DJ‐1 as a potential mediator of IPC has been investigated in our recently published experimental studies . In the present study, this is again confirmed by the better cell viability with the less LDH release in DJ‐1 overexpressing H9c2 cells subjected to H/R and disappeared cardioprotection of DHP in DJ‐1 knockdown H9c2 cells.…”

“…31,32 Notably, the important role of DJ-1 as a potential mediator of IPC has been investigated in our recently published experimental studies. 9,10,33 In the present study, this is again confirmed by the better cell viability with the less LDH release in DJ-1 overexpressing H9c2 cells subjected to H/R and disappeared cardioprotection of DHP in DJ-1 knockdown H9c2 cells. Moreover, the present study also showed that DHP attenuated H/R-induced oxidative stress in a DJ-1-dependent way.…”

Metformin attenuates myocardial ischemia-reperfusion injury via up-regulation of antioxidant enzymes

“…Excessive generation of ROS is involved in several detrimental processes, including cell death and apoptosis triggered by the opening of the mitochondrial permeability transition pores (mPTP) [ 6 , 7 ]. Antioxidant agents can effectively decrease generation of ROS, therefore, antioxidant therapy, especially activation of endogenous antioxidant enzymes, such as catalase and manganese superoxide dismutase (MnSOD) seems to be a potential therapeutic approach for myocardial IR injury [ 8 , 9 ].…”

Molecular Mechanism Underlying Hypoxic Preconditioning-Promoted Mitochondrial Translocation of DJ-1 in Hypoxia/Reoxygenation H9c2 Cells

“…The important role of DJ-1 as a potential mediator of HPC has been investigated in ours previous published experimental works, and studies have shown that DJ-1 is implicated in the cardioprotection of HPC against H/R-induced oxidative stress damage [6,8,25]. Interestingly, our recent studies have demonstrated that DJ-1-mediated cardioprotection is related to preserving mitochondrial complex I activity and subsequently inhibiting mitochondrial ROS generation [15].…”

“…A wealth of information has been collected on the molecular mechanisms involved in ischemic preconditioning, but many aspects of the signaling pathways and of the end effectors of the cardioprotection remain unknown [2,4,5]. An intriguing and unresolved aspect is the involvement of DJ-1 in the genesis of preconditioning [6][7][8].…”