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NFκB promotes oxidative stress-induced necrosis and ischemia/reperfusion injury by inhibiting Nrf2-ARE pathway.

ABSTRACT: In this study, we identified an unexpected pro-cell death role for NFκB in mediating oxidative stress-induced necrosis, and provide new mechanistic evidence that NFκB, in cooperation with HDAC3, negatively regulates Nrf2-ARE anti-oxidative signaling through transcriptional silencing. We showed that genetic inactivation of NFκB-p65 inhibited, whereas activation of NFκB promoted, oxidative stress-induced cell death and HMGB1 release, a biomarker of necrosis. Moreover, NFκB-luciferase activity was elevated in cardiomyocytes after simulated ischemia/reperfusion (sI/R) or doxorubicin (DOX) treatment, and inhibition of NFκB with Ad-p65-shRNA or Ad-IκBαM diminished sI/R- and DOX-induced cell death and HMGB1 release. Importantly, NFκB negatively regulated Nrf2-ARE activity and the expression of antioxidant proteins. Mechanistically, co-immunoprecipitation revealed that p65 was required for Nrf2-HDAC3 interaction and transcriptional silencing of Nrf2-ARE activity. Further, the ability of HDAC3 to repress Nrf2-ARE activity was lost in p65 deficient cells. Pharmacologic inhibition of HADCs or NFκB with trichostatin A (TSA) or BMS-345541, respectively, increased Nrf2-ARE activity and promoted cell survival after sI/R. In vivo, NFκB transcriptional activity in the mouse heart was significantly elevated after ischemia/reperfusion (I/R) injury, which was abolished by cardiomyocyte-specific deletion of p65 using p65^fl/flNkx2.5-Cre mice. Moreover, genetic ablation of p65 in the mouse heart attenuated myocardial infarct size after acute I/R injury and improved cardiac remodeling and functional recovery after chronic myocardial infarction. Thus, our results identified NFκB as a key regulator of oxidative stress-induced necrosis by suppressing the Nrf2-ARE antioxidant pathway through an HDAC3-dependent mechanism. This study also revealed a new pathogenic role of NFκB in cardiac ischemic injury and pathological remodeling.

SUBMITTER: Guo X

PROVIDER: S-EPMC7530060 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Liver ischemia-reperfusion injury (IRI) is a common clinical event with high morbidity in patients undergoing complex liver surgery or having abdominal trauma. Inflammatory and oxidative stress responses are the main contributing factors in liver IRI. The iridoid glucoside aucubin (AU) has good anti-inflammatory and antioxidative effects; however, there are no relevant reports on the protective effect of glucosides on hepatic IRI. The purpose of this study was to determine whether AU pretreatment could prevent liver IRI and to explore the mechanism. Sprague-Dawley rats were randomly divided into five groups. The sham operation and IRI control groups were given intraperitoneal injections of normal saline, while the AU low-dose (AU-L) group, AU medium-dose (AU-M) group, and AU high-dose (AU-H) group were given intraperitoneal injections of AU at doses of 1, 5, and 10 mg/kg/day, respectively. After 10 d, liver IRI (70% liver ischemia for 1 h, reperfusion for 6 h) was surgically established in all groups except the sham group. Our results confirmed that liver injury was significantly aggravated after hepatic ischemia-reperfusion. AU alleviated the increase of transaminase and pathological changes induced by ischemia-reperfusion and improved liver damage. AU could also ameliorate the inflammatory and oxidative stress responses induced by ischemia-reperfusion and reduced expression of high mobility group protein (HMG)B1, receptor for advanced glycation end-products (RAGE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and reactive oxygen species (ROS). Moreover, AU reduced ischemia-reperfusion-induced mitochondrial dysfunction and cells apoptosis, increased peroxisome proliferator-activated receptor γ coactivator (PGC)-1α and uncoupling (UCP)2 protein expression, and reduced caspase-3, cleaved caspase-3, and Cytochrome P450 proteins (CYP) expression. To determine expression levels of the Toll-like receptor (TLR)-4/nuclear factor-κB (NF-κB) pathway-related proteins in vitro and in vivo, we also measured TLR-4, myeloid differentiation factor88 (MyD88), NF-κB P65, p-P65, I-kappa-B-alpha (IκB-α), and p-IκB-α levels. The results showed that AU effectively inhibited activation of the TLR-4/NF-κB signaling pathway. In conclusion, we showed for the first time a hepatoprotective effect for AU in liver IRI, which acted by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway, oxidative stress, and apoptosis. Pretreatment with AU may be a promising strategy for preventing liver IRI.

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NFκB promotes oxidative stress-induced necrosis and ischemia/reperfusion injury by inhibiting Nrf2-ARE pathway.

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