Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for hypoxic preconditioning-mediated delayed cardioprotection.
It has been well demonstrated that hypoxic preconditioning (HPC) can attenuate hypoxia/reoxygenation (H/R)-induced oxidant stress and elicit delayed cardioprotection by upregulating the expression of multiple antioxidative enzymes such as heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD) and so on. However, the underlying mechanisms of HPC-induced upregulation of antioxidative enzymes are not fully understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element (ARE) and plays a crucial role in cellular defence against oxidative stress. Here, we wondered whether activation of the Nrf2-ARE pathway is responsible for the induction of antioxidative enzymes by HPC and contributes to the delayed cardioprotection of HPC. Cellular model of HPC from rat heart-derived H9c2 cells was induced 24 h prior to H/R. The results showed that HPC efficiently attenuated H/R-induced viability loss and lactate dehydrogenase leakage. In addition, HPC increased nuclear translocation and ARE binding of Nrf2 during the late phase, upregulated the expression of antioxidative enzymes (HO-1 and MnSOD), inhibited H/R-induced oxidant stress. However, when Nrf2 was specifically knocked down by siRNA, the induction of antioxidative enzymes by HPC was completely abolished and, as a result, the inhibitory effect of HPC on H/R-induced oxidant stress was reversed, and the delayed cardioprotection induced by HPC was also abolished. These results suggest that HPC upregulates antioxidative enzymes through activating the Nrf2-ARE pathway and confers delayed cardioprotection against H/R-induced oxidative stress.
The Key Laboratory of Basic Pharmacology, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, People's Republic of China.
Xiao-Shan
XS
Huang
He-Ping
HP
Chen
Hai-Hong
HH
Yu
Yu-Feng
YF
Yan
Zhang-Ping
ZP
Liao
Qi-Ren
QR
Huang
D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics; D000975:Antioxidants / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D055785:Gene Knockdown Techniques; D019157:Ischemic Preconditioning, Myocardial; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction; D013312:Stress, Physiological; D015854:Up-Regulation
D000975:Antioxidants; D002316:Cardiotonic Agents; D051267:NF-E2-Related Factor 2