scholarly journals Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 349 ◽  
Author(s):  
Denise Peserico ◽  
Chiara Stranieri ◽  
Ulisse Garbin ◽  
Chiara Mozzini C ◽  
Elisa Danese ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Cultured Cells ◽  
Ischemia Reperfusion ◽  
Cholesterol Absorption ◽  
Antioxidant Response ◽  
Related Factor ◽  
Cellular Models ◽  
Compound C ◽  
Cholesterol Absorption Inhibitor

Background: While reperfusion is crucial for survival after an episode of ischemia, it also causes oxidative stress. Nuclear factor-E2-related factor 2 (Nrf2) and unfolded protein response (UPR) are protective against oxidative stress and endoplasmic reticulum (ER) stress. Ezetimibe, a cholesterol absorption inhibitor, has been shown to activate the AMP-activated protein kinase (AMPK)/Nrf2 pathway. In this study we evaluated whether Ezetimibe affects oxidative stress and Nrf2 and UPR gene expression in cellular models of ischemia-reperfusion (IR). Methods: Cultured cells were subjected to simulated IR with or without Ezetimibe. Results: IR significantly increased reactive oxygen species (ROS) production and the percentage of apoptotic cells without the up-regulation of Nrf2, of the related antioxidant response element (ARE) gene expression or of the pro-survival UPR activating transcription factor 6 (ATF6) gene, whereas it significantly increased the pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP). Ezetimibe significantly decreased the cellular ROS formation and apoptosis induced by IR. These effects were paralleled by the up-regulation of Nrf2/ARE and ATF6 gene expression and by a down-regulation of CHOP. We also found that Nrf2 activation was dependent on AMPK, since Compound C, a pan inhibitor of p-AMPK, blunted the activation of Nrf2. Conclusions: Ezetimibe counteracts IR-induced oxidative stress and induces Nrf2 and UPR pathway activation.

scholarly journals Sanghuangporus sanghuang Mycelium Prevents Paracetamol-Induced Hepatotoxicity through Regulating the MAPK/NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt and CaMKKβ/LKB1/AMPK Pathways and Suppressing Oxidative Stress and Inflammation

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 897
Author(s):  
Wen-Ping Jiang ◽  
Jeng-Shyan Deng ◽  
Shyh-Shyun Huang ◽  
Sheng-Hua Wu ◽  
Chin-Chu Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1 ◽  
Molecular Evidence ◽  
Related Factor ◽  
Serum Aminotransferase ◽  
Compound C

Liver damage induced by paracetamol overdose is the main cause of acute liver failure worldwide. In order to study the hepatoprotective effect of Sanghuangporus sanghuang mycelium (SS) on paracetamol-induced liver injury, SS was administered orally every day for 6 days in mice before paracetamol treatment. SS decreased serum aminotransferase activities and the lipid profiles, protecting against paracetamol hepatotoxicity in mice. Furthermore, SS inhibited the lipid peroxidation marker malondialdehyde (MDA), hepatic cytochrome P450 2E1 (CYP2E1), and the histopathological changes in the liver and decreased inflammatory activity by inhibiting the production of proinflammatory cytokines in paracetamol-induced acute liver failure. Moreover, SS improved the levels of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase in the liver. Significantly, SS diminished mitogen-activated protein kinase (MAPK), Toll-like receptor 4 (TLR4), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and the nuclear factor-kappa B (NF-κB) axis, as well as upregulated the Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, in paracetamol-induced mice. SS mainly inhibited the phosphorylation of the liver kinase B1 (LKB1), Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ), and AMP-activated protein kinase (AMPK) protein expression. Furthermore, the protective effects of SS on paracetamol-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. In summary, we provide novel molecular evidence that SS protects liver cells from paracetamol-induced hepatotoxicity by inhibiting oxidative stress and inflammation.

Neuroprotection of chromobox 7 knockout in the mouse after cerebral ischemia-reperfusion injury via nuclear factor E2-related factor 2/hemeoxygenase-1 signaling pathway

2021 ◽  
pp. 096032712110361
Author(s):  
Hai-Tao Zhang ◽  
Xi-Zeng Wang ◽  
Qing-Mei Zhang ◽  
Han Zhao
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Water Content ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cerebral Ischemia Reperfusion ◽  
And Oxidative Stress

Objective To explore the mechanism of chromobox 7 (CBX7)-mediated nuclear factor E2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling pathway in the cerebral ischemia/reperfusion (I/R) injury. Methods The experimental wild-type (WT) and CBX7-/- mice were used to establish cerebral I/R models using the middle cerebral artery occlusion (MCAO) surgery to determine CBX7 levels at different time points after MCAO injury. For all mice, neurological behavior, infarct size, water content, and oxidative stress–related indicators were determined, and transferase (TdT)-mediated dUTP-biotin nick-end labeling (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)) staining method was employed to observe cell apoptosis, while Western blot to measure the expression of CBX7 and Nrf/HO-1 pathway-related proteins. Results At 6 h, 12 h, 24 h, 3 days, and 7 days after mice with MCAO, CBX7 expression was gradually up-regulated and the peak level was reached at 24 h. Mice in the WT + MCAO group had increased infarct size, with significant increases in the modified neurological severity scores and water content in the brain, as well as the quantity of TUNEL-positive cells. For the oxidative stress-indicators, an increase was seen in the content of MDA (malondial dehyde), but the activity of SOD (superoxide dismutase) and content of GSH-PX (glutathione peroxidase) and CAT (catalase) were decreased; meanwhile, the protein expression of CBX7, HO-1, and nuclear Nrf2 was up-regulated, while the cytoplasmic Nrf2 was down-regulated. Moreover, CBX7 knockout attenuated I/R injury in mice. Conclusion Knockout of CBX7 may protect mice from cerebral I/R injury by reducing cell apoptosis and oxidative stress, possibly via activating the Nrf2/HO-1 pathway.

scholarly journals Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yasuhiro Nakagami
Keyword(s):  
Oxidative Stress ◽  
Neuronal Degeneration ◽  
Antioxidant Response ◽  
Related Factor ◽  
Retinal Diseases ◽  
Age Related ◽  
Nrf2 Signaling Pathway ◽  
Genes Encoding ◽  
Antioxidant Response Elements ◽  
Nrf2 Activator

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of Nrf2 functions is one of the critical defensive mechanisms against oxidative stress in many species. The retina is constantly exposed to reactive oxygen species, and oxidative stress is a major contributor to age-related macular diseases. Moreover, the resulting inflammation and neuronal degeneration are also related to other retinal diseases. The well-known Nrf2 activators, bardoxolone methyl and its derivatives, have been the subject of a number of clinical trials, including those aimed at treating chronic kidney disease, pulmonary arterial hypertension, and mitochondrial myopathies. Recent studies suggest that Nrf2 activation protects the retina from retinal diseases. In particular, this is supported by the finding that Nrf2 knockout mice display age-related retinal degeneration. Moreover, the concept has been validated by the efficacy of Nrf2 activators in a number of retinal pathological models. We have also recently succeeded in generating a novel Nrf2 activator, RS9, using a biotransformation technique. This review discusses current links between retinal diseases and Nrf2 and the possibility of treating retinal diseases by activating the Nrf2 signaling pathway.

scholarly journals Safflor Yellow B Attenuates Ischemic Brain Injury via Downregulation of Long Noncoding AK046177 and Inhibition of MicroRNA-134 Expression in Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Chaoyun Wang ◽  
Hongzhi Wan ◽  
Qiaoyun Wang ◽  
Hongliu Sun ◽  
Yeying Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Ischemia Reperfusion ◽  
Cell Activity ◽  
Neuronal Injury ◽  
The Body ◽  
Ros Generation ◽  
Related Factor ◽  
Cell Respiration ◽  
Oxidative Balance

Stroke breaks the oxidative balance in the body and causes extra reactive oxygen species (ROS) generation, leading to oxidative stress damage. Long noncoding RNAs (lncRNAs) and microRNAs play pivotal roles in oxidative stress-mediated brain injury. Safflor yellow B (SYB) was able to effectively reduce ischemia-mediated brain damage by increasing antioxidant capacity and inhibiting cell apoptosis. In this study, we investigated the putative involvement of lncRNA AK046177 and microRNA-134 (miR-134) regulation in SYB against ischemia/reperfusion- (I/R-) induced neuronal injury. I/R and oxygen-glucose deprivation/reoxygenation (OGD/R) were established in vivo and in vitro. Cerebral infarct volume, neuronal apoptosis, and protein expression were detected. The effects of SYB on cell activity, cell respiration, nuclear factor erythroid 2-related factor 2 (Nrf2), antioxidant enzymes, and ROS were evaluated. I/R or OGD/R upregulated the expression of AK046177 and miR-134 and subsequently inhibited the activation and expression of CREB, which caused ROS generation and brain/cell injury. SYB attenuated the effects of AK046177, inhibited miR-134 expression, and promoted CREB activation, which in turn promoted Nrf2 expression, and then increased antioxidant capacities, improved cell respiration, and reduced apoptosis. We suggested that the antioxidant effects of SYB were driven by an AK046177/miR-134/CREB-dependent mechanism that inhibited this pathway, and that SYB has potential use in reducing or possibly preventing I/R-induced neuronal injury.

scholarly journals Astragaloside IV Protects Against Oxidative Stress in Calf Small Intestine Epithelial Cells via NFE2L2-Antioxidant Response Element Signaling

2019 ◽  
Vol 20 (24) ◽  
pp. 6131 ◽  
Author(s):  
Yafang Wang ◽  
Fugui Jiang ◽  
Haijian Cheng ◽  
Xiuwen Tan ◽  
Yifan Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Small Intestine ◽  
Epithelial Cells ◽  
Reactive Oxygen Species Generation ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Antioxidant Response Element ◽  
Astragaloside Iv ◽  
Response Element

Oxidative stress can damage intestinal epithelial cell integrity and function, causing gastrointestinal disorders. Astragaloside IV (ASIV) exhibits a variety of biological and pharmacological properties, including anti-inflammatory and antioxidant effects. The purpose of this research was to investigate the cytoprotective action of ASIV and its mechanisms in calf small intestine epithelial cells with hydrogen peroxide (H2O2)-induced oxidative stress. ASIV pretreatment not only increased cell survival, but it also decreased reactive oxygen species generation and apoptosis, enhanced superoxide dismutase, catalase, and glutathione peroxidase levels, and it reduced malondialdehyde formation. Furthermore, pretreatment with ASIV elevated the mRNA and protein levels of nuclear factor erythroid 2-related factor 2 (NFE2L2), heme oxygenase-1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1). The NFE2L2 inhibitor ML385 inhibited NFE2L2 expression and then blocked HMOX1 and NQO1 expression. These results demonstrate that ASIV treatment effectively protects against H2O2-induced oxidative damage in calf small intestine epithelial cells through the activation of the NFE2L2-antioxidant response element signaling pathway.

The novel Nrf2-interacting factor KAP1 regulates susceptibility to oxidative stress by promoting the Nrf2-mediated cytoprotective response

2011 ◽  
Vol 436 (2) ◽  
pp. 387-397 ◽  
Author(s):  
Atsushi Maruyama ◽  
Keizo Nishikawa ◽  
Yukie Kawatani ◽  
Junsei Mimura ◽  
Tomonori Hosoya ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cultured Cells ◽  
Affinity Purification ◽  
Regulatory Region ◽  
Nuclear Accumulation ◽  
Related Factor ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Quinone Oxidoreductase ◽  
Nih 3T3

The transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) co-ordinately regulates ARE (antioxidant-response element)-mediated induction of cytoprotective genes in response to electrophiles and oxidative stress; however, the molecular mechanism controlling Nrf2-dependent gene expression is not fully understood. To identify factors that regulate Nrf2-dependent transcription, we searched for proteins that interact with the Nrf2-NT (N-terminal Nrf2 transactivation domain) by affinity purification from HeLa nuclear extracts. In the present study, we identified KAP1 [KRAB (Krüppel-associated box)-associated protein 1] as a novel Nrf2-NT-interacting protein. Pull-down analysis confirmed the interaction between KAP1 and Nrf2 in cultured cells and demonstrated that the N-terminal region of KAP1 binds to Nrf2-NT in vitro. Reporter assays showed that KAP1 facilitates Nrf2 transactivation activity in a dose-dependent manner. Furthermore, the induction of the Nrf2-dependent expression of HO-1 (haem oxygenase-1) and NQO1 [NAD(P)H quinone oxidoreductase 1] by DEM (diethyl maleate) was attenuated by KAP1 knockdown in NIH 3T3 fibroblasts. This finding established that KAP1 acts as a positive regulator of Nrf2. Although Nrf2 nuclear accumulation was unaffected by KAP1 knockdown, the ability of Nrf2 to bind to the regulatory region of HO-1 and NQO1 was reduced. Moreover, KAP1 knockdown enhanced the sensitivity of NIH 3T3 cells to tert-butylhydroquinone, H2O2 and diamide. These results support our contention that KAP1 participates in the oxidative stress response by maximizing Nrf2-dependent transcription.

scholarly journals Nrf2and Cardiovascular Defense

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Reuben Howden
Keyword(s):  
Cardiovascular Diseases ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
Antioxidant Response ◽  
Positive Outcome ◽  
Cellular Damage ◽  
Antioxidant Defenses ◽  
Related Factor ◽  
Transcription Factor Nuclear Factor

The cardiovascular system is susceptible to a group of diseases that are responsible for a larger proportion of morbidity and mortality than any other disease. Many cardiovascular diseases are associated with a failure of defenses against oxidative stress-induced cellular damage and/or death, leading to organ dysfunction. The pleiotropic transcription factor, nuclear factor-erythroid (NF-E) 2-related factor 2 (Nrf2), regulates the expression of antioxidant enzymes and proteins through the antioxidant response element.Nrf2is an important component in antioxidant defenses in cardiovascular diseases such as atherosclerosis, hypertension, and heart failure.Nrf2is also involved in protection against oxidant stress during the processes of ischemia-reperfusion injury and aging. However, evidence suggests thatNrf2activity does not always lead to a positive outcome and may accelerate the pathogenesis of some cardiovascular diseases (e.g., atherosclerosis). The precise conditions under whichNrf2acts to attenuate or stimulate cardiovascular disease processes are unclear. Further studies on the cellular environments related to cardiovascular diseases that influenceNrf2pathways are required beforeNrf2can be considered a therapeutic target for the treatment of cardiovascular diseases.

scholarly journals Differential Yet Integral Contributions of Nrf1 and Nrf2 in the Human HepG2 Cells on Antioxidant Cytoprotective Response against Tert-Butylhydroquinone as a Pro-Oxidative Stressor

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1610
Author(s):  
Reziyamu Wufuer ◽  
Zhuo Fan ◽  
Keli Liu ◽  
Yiguo Zhang
Keyword(s):  
Oxidative Stress ◽  
Regulatory Networks ◽  
Substantial Reduction ◽  
Normal Growth ◽  
Antioxidant Response ◽  
Related Factor ◽  
Nuclear Factor ◽  
Expression Levels ◽  
Hormetic Effect ◽  
Cytoprotective Response

In the past 25 years, Nrf2 (nuclear factor erythroid 2-related factor 2, also called NFE2L2) had been preferentially parsed as a master hub of regulating antioxidant, detoxification, and cytoprotective genes; albeit as a matter of fact that Nrf1 (nuclear factor erythroid 2-related factor 1, also called NFE2L1)—rather than Nrf2—is indispensable for cell homeostasis and organ integrity during normal growth and development. Herein, distinct genotypic cell lines (i.e., Nrf1α−/−, Nrf2−/−ΔTA, and caNrf2ΔN) are employed to determine differential yet integral roles of Nrf1 and Nrf2 in mediating antioxidant responsive genes to tert-butylhydroquinone (tBHQ) serving as a pro-oxidative stressor. In Nrf1α−/− cells, Nrf2 was highly accumulated but also could not fully compensate specific loss of Nrf1α’s function in its basal cytoprotective response against endogenous oxidative stress, though it exerted partially inducible antioxidant response, as the hormetic effect of tBHQ, against apoptotic damages. By contrast, Nrf2−/−ΔTA cells gave rise to a substantial reduction of Nrf1 in both basal and tBHQ-stimulated expression levels and hence resulted in obvious oxidative stress, but it can still be allowed to mediate a potent antioxidant response, as accompanied by a significantly decreased ratio of GSSG (oxidized glutathione) to GSH (reduced glutathione). Conversely, a remarkable increase of Nrf1 expression resulted from the constitutive active caNrf2ΔN cells, which were not manifested with oxidative stress, whether or not it was intervened with tBHQ. Such inter-regulatory effects of Nrf1 and Nrf2 on the antioxidant and detoxification genes (encoding HO-1, NQO1, GCLC, GCLM, GSR, GPX1, TALDO, MT1E, and MT2), as well on the ROS (reactive oxygen species)-scavenging activities of SOD (superoxide dismutase) and CAT (catalase), were further investigated. The collective results unraveled that Nrf1 and Nrf2 make distinctive yet cooperative contributions to finely tuning basal constitutive and/or tBHQ-inducible expression levels of antioxidant cytoprotective genes in the inter-regulatory networks. Overall, Nrf1 acts as a brake control for Nrf2’s functionality to be confined within a certain extent, whilst its transcription is regulated by Nrf2.

Abstract 17514: Hydrogen Sulfide Levels and NRF2 Activity are Attenuated in the Setting of Critical Limb Ischemia (CLI)

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kazi N Islam ◽  
David J Polhemus ◽  
Erminia Donnarumma ◽  
Hiroyuki Otsuka ◽  
Shashi Bhushan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Hydrogen Sulfide ◽  
Limb Ischemia ◽  
Antioxidant Response ◽  
Protein Carbonyl ◽  
Related Factor ◽  
Mobility Shift ◽  
Protein Levels ◽  
Nrf2 Activation

Background: Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythriod 2-related factor 2 (NRF2) is responsible for the expression of antioxidant response element (ARE)-regulated genes and is known to be upregulated by H2S. We examined the levels of H2S producing enzymes, H2S, and NRF2 activation status in skeletal muscle obtained from CLI patients. Methods: Gastrocnemius tissues were attained post amputation from human CLI and aged-matched control patients. Tissue H2S levels were measured using gas chromatography methods coupled with sulfur chemiluminescence. RT-qPCR, immunoblot, and electrophoretic mobility shift assay (EMSA) were used to analyze respective gene expression, protein levels, and DNA binding activity, respectively. Results: We found mRNA and protein levels of CSE, CBS, and 3-MST were significantly decreased in skeletal muscle of CLI (~2 fold, p < 0.05) patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in NRF2 activation (2 fold, p < 0.05) as well as antioxidant proteins, such as CuZn-superoxide dismutase (2 fold, p < 0.05), catalase (2 fold, p < 0.05), and glutathione peroxidase (2 fold, p < 0.05) in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation were significantly increased (2 fold, p < 0.05) in skeletal muscle of CLI patients as compared to age-matched controls. Conclusions: The data demonstrate that H2S bioavailability and NRF2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S producing enzymes may contribute to the pathogenesis of CLI.

Abstract P317: Acute Exercise Stress and ROS Signaling: Activation of Nrf2/ARE-Dependent Antioxidant Defense Mechanisms in the Mouse Myocardium

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Corey J Miller ◽  
Kalavathy Ramachandran ◽  
Gayatri D Khanderao ◽  
Sankaranarayanan Kannan ◽  
Vasanthi Rajasekaran ◽  
...  
Keyword(s):  
Defense Mechanisms ◽  
Acute Exercise ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion ◽  
Antioxidant Response ◽  
Exercise Stress ◽  
Related Factor ◽  
Paramagnetic Resonance ◽  
Antioxidant Genes ◽  
Age Dependent

Background: Cellular defense mechanisms are crucial for maintaining intracellular redox state and mitigating free radical accumulation with aging. Nuclear Erythroid 2 p45 related factor-2 (Nrf2) regulates basal and inducible expression of numerous cytoprotective/antioxidant genes. We hypothesize that acute exercise will induce ROS, which triggers Nrf2/ARE signaling and promotes myocardial defense mechanisms. Methods: Age-matched wild-type (WT) and Nrf2−/− (KO) mice at 2 and >20 months were subjected to acute exercise stress (AES) and then we assessed the activation of Nrf2/ARE-dependent transcriptional mechanisms in the heart. Myocardial ROS was measured by electron paramagnetic resonance (EPR) analysis. Results: Under basal conditions, total ROS and GSH levels were identical at 2 months, whereas they were significantly impaired in Nrf2-KO when compared to Wt myocardium at ∼20 months indicating that Nrf2-deficiency is coupled with blemished redox potential. Upon AES, the young WT and KO mice exhibited oxidative stress (OS), but the WT were able compensate for the stress by increasing Nrf2 nuclear translocation and subsequent upregulation of cytoprotective genes. However, the aged (WT & KO) mice developed OS in response to AES. The degree of OS was several fold higher in the aged Nrf2-KO mice when compared with WT, suggesting an important age dependent function for Nrf2 in the myocardium. Western blot analysis revealed significant down regulation of major antioxidants (GCS, Nqo1, Ho1, catalase, G6pd and Gsr) in KO mice, while WT mice exhibited compensatory antioxidant response to the AES. Gene expression (qPCR) analysis revealed profound upregulation of major antioxidants in WT, but there was no such response occurred in KO mice after AES, suggesting Nrf2 independent mechanisms are inadequate to protect the myocardium. Conclusions: Acute exercise induces ROS and thereby activates Nrf2 in the myocardium. However, disruption of Nrf2 increases susceptibility of the myocardium to OS induced damage. Thus Nrf2 signaling might be a potential therapeutic target to protect the heart from ROS and/or age dependent ischemia/reperfusion (I/R) injury and myocardial infarction (MI).

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