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.

Ischemic Postconditioning Alleviates Intestinal Ischemia-Reperfusion Injury by Enhancing Autophagy and Suppressing Oxidative Stress through the Akt/GSK-3β/Nrf2 Pathway in Mice

“…Activation of the Nrf2-ARE signaling pathway prevents hyperphosphatemiainduced vascular calcification by inducing autophagy in renal vascular smooth muscle cells [33]. The protective effects of triterpenoid CDDO-imidazole against liver IR injury are attributed to enhanced autophagy, which is mediated by the activation of the Nrf2/HO-1 pathway [34]. In recent years, many studies showed that phosphorylated p62 competitively binds to the KEAP1, activating Nrf2, and creates a positive feedback loop in the p62-Nrf2-KEAP1 pathway [35].…”

Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses

“…Zinc protoporphyrin (ZnPP), an inhibitor of HO‐1, diminished the effect of OA . The activation of Nrf2/HO‐1 pathways is also involved in the OA derivative CDDO‐Im protection against hepatic IR injury …”

Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway

“…Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor in the cap 'n' collar family, regulates the constitutive and inducible expression of a variety of genes involved in drug metabolism, detoxification, and antioxidative defenses [13]. It also plays an important role in cellular redox homeostasis through inducing more than 250 genes, including heme oxygenase 1 (HO-1), NAD(P)H: quinine oxidoreductase 1 (NQO1), and the γ-glutamyl cysteine synthetase catalytic subunit (GCLC) and modifier subunit (GCLM) [14].…”