The triterpenoid CDDO-imidazolide ameliorates mouse liver ischemia-reperfusion injury through activating the Nrf2/HO-1 pathway enhanced autophagy.

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidants has been implicated to have protective roles in ischemia-reperfusion (I/R) injury in many animal models. However, the in vivo effects of CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole), a Nrf2 activator, in hepatic I/R injury is lacking and its exact molecular mechanisms are still not very clear. The goals of this study were to determine whether CDDO-Im can prevent liver injury induced by I/R in the mouse, and to elucidate the molecular target of drug action. Mice were randomly equally divided into two groups and administered intraperitoneally with either DMSO control or CDDO-Im (2 mg/kg) 3 h before subjected to 90-min hepatic 70% ischemia followed by reperfusion. Subsequently, the Liver and blood samples of these mice were collected to evaluate liver injury. CDDO-Im pretreatment markedly improve hepatic I/R injury by attenuating hepatic necrosis and apoptosis, reducing reactive oxygen species (ROS) levels and inflammatory responses, and ameliorating mitochondrial dysfunction. Mechanistically, by using Nrf2 Knockout mice and hemeoxygenase 1 (HO-1) inhibitor, we found that these CDDO-Im protection effects are attributed to enhanced autophagy, which is mediated by activating Nrf2/HO-1 pathway. By accelerating autophagy and clearance of damaged mitochondria, CDDO-Im reduced the mtDNA release and ROS overproduction, and in turn decreased damage-associated molecular patterns induced inflammatory responses and the following secondary liver injury. These results indicate that by enhancing autophagy, CDDO-Im-mediated activation of Nrf2/HO-1 signaling could be a novel therapeutic strategy to minimize the adverse effects of hepatic I/R injury.

• Authors: Dongwei Xu, Lili Chen, Xiaosong Chen, Yankai Wen, Chang Yu, Jufang Yao, Hailong Wu, Xin Wang, Qiang Xia, Xiaoni Kong
• Journal: Cell death & disease (Cell Death Dis) Vol. 8 Issue 8 Pg. e2983 (08 10 2017) ISSN: 2041-4889 [Electronic] England
• PMID: 28796242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• DNA, Mitochondrial
• Imidazoles
• NF-E2-Related Factor 2
• Reactive Oxygen Species
• Oleanolic Acid
• Heme Oxygenase-1

Topics

• Animals
• Autophagy (drug effects)
• Blotting, Western
• Cells, Cultured
• DNA, Mitochondrial (genetics)
• Enzyme-Linked Immunosorbent Assay
• Heme Oxygenase-1 (metabolism)
• Hepatocytes (drug effects, metabolism)
• Imidazoles (therapeutic use)
• In Situ Nick-End Labeling
• Liver (drug effects, metabolism)
• Liver Diseases (drug therapy, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microscopy, Electron, Transmission
• NF-E2-Related Factor 2 (metabolism)
• Oleanolic Acid (analogs & derivatives, therapeutic use)
• RNA Interference
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)