DJ-1 Mediates the Delayed Cardioprotection of Hypoxic Preconditioning Through Activation of Nrf2 and Subsequent Upregulation of Antioxidative Enzymes.
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.
The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, China.
Yu-Feng
YF
Yan
He-Ping
HP
Chen
Xiao-Shan
XS
Huang
Ling-Yu
LY
Qiu
Zhang-Ping
ZP
Liao
Qi-Ren
QR
Huang
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
D000975:Antioxidants; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; C404267:PARK7 protein, rat; D000071617:Protein Deglycase DJ-1