Effect of Heme Oxygenase-1 Overexpression in Two Models of Lung Inflammation

2003 ◽  
Vol 228 (5) ◽  
pp. 442-446 ◽  
Author(s):  
A. Zampetaki ◽  
T. Minamino ◽  
S.A. Mitsialis ◽  
S. Kourembanas
Keyword(s):  
Transgenic Mice ◽  
Heme Oxygenase ◽  
Lung Inflammation ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Wild Type ◽  
Pronounced Increase ◽  
Protein Levels ◽  
Cytokines And Chemokines ◽  
Genetically Engineered Mice

An increasing number of studies implicate heme oxygenase-1 (HO-1) in the regulation of inflammation. Although the mechanisms involved in this cytoprotection are largely unknown, HO-1 and its enzymatic products, carbon monoxide and bilirubin, downregulate the inflammatory response by either attenuating the expression of adhesion molecules and thus inhibiting leukocyte recruitment or by repressing the induction of cytokines and chemokines. In the present study we used genetically engineered mice that express high levels of a human cDNA HO-1 transgene in lung epithelium to assess the effect of HO-1 on lung inflammation. Two separate models of inflammation were studied: hypoxic exposure and lipopolysaccharide (LPS) challenge. We found that both mRNA and protein levels of specific cytokines and chemokines were significantly elevated in response to hypoxia in the lungs of wild-type mice after 2 and 5 days of exposure but significantly suppressed in the hypoxic lungs of transgenic mice, suggesting that inhibition of these cytokines was caused by overexpression of HO-1. However, LPS treatment resulted in a very pronounced increase in mRNA levels of several cytokines in both wild-type and transgenic mice. Despite the high mRNA levels, significantly lower cytokine protein levels were detected in the bronchoalveolar lavage of HO-1 overexpressing mice compared with wild type, indicating that HO-1 leads to repression of cytokines in the airway. These results demonstrate that HO-1 activity operates through distinct molecular mechanisms to confer cytoprotection in the hypoxic and the LPS models of inflammation.

Synergistic Up-Regulation of Heme Oxygenase-1 in Human Liver by Heme and siRNA to Bach1:Possible Therapeutic Implications.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1633-1633
Author(s):  
Tahereh Ghaziani ◽  
Ying Shan ◽  
Richard W. Lambrecht ◽  
Herbert L. Bonkovsky
Keyword(s):  
Gene Expression ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Negative Regulator ◽  
Heme Oxygenase 1 ◽  
Significant Finding ◽  
Mrna Levels ◽  
Protein Levels

Abstract Background: Heme oxygenase-1 (HO-1) is an antioxidant defense enzyme that converts toxic heme into antioxidants. HO-1 is strongly up-regulated by its physiologic substrate, heme, which is currently the treatment of choice for acute attacks of porphyria and which may have other therapeutic uses, as well (e.g., for cytoprotection or amelioration of ischemia/reperfusion injury by increasing supply of carbon monoxide, biliverdin, or bilirubin). Up-regulation of HO-1 expression has been associated with increased resistance to tissue injury. Bach1 is a bZip protein which forms heterodimers with small Maf proteins. HO-1 is expressed at higher levels in tissues of Bach1-deficient mice, indicating that Bach1 acts as a negative regulator of the mouse HO-1 gene. The molecular mechanism that confers repression of HO-1 by Bach1, and whether there are similar effects in human cells, has remained elusive. The aim of this study was to assess whether modulation of human hepatic Bach1 expression by siRNA technology influences HO-1 gene expression and whether such gene silencing would enhance the inducing effects of heme on HO-1. Methods: siRNAs targeted 4 different positions of human Bach1 mRNA were designed and synthesized. We transfected Bach1-siRNA (25–200 nM) into Huh-7 cells using Lipofectamine for 24–72 h, after which, cells were treated with or without heme. We quantified HO-1 and Bach1 mRNA and protein levels by quantitative RT-PCR and western blotting, respectively. Effects and specificity of Bach1-siRNA were analyzed and compared with those of non-Bach1 related siRNAs (non-specific control-duplex (NSCD) and LaminB2-siRNA). Results: Bach1-siRNAs (25–200 nM) transfected into Huh-7 cells for 24–72 h significantly reduced Bach1 mRNA and protein levels approximately 80%, compared with non siRNA treated cells. In contrast, transfection with same amounts of NSCD or LaminB2 siRNA did not reduce Bach1 mRNA or protein levels, confirming the specificity of Bach1-siRNA in Huh-7 cells. A significant finding of these studies was the 7-fold up-regulation of the HO-1 gene in Bach1-siRNA transfected cells, compared to cells without Bach1-siRNA or those transfected with NSCD or LaminB2. Bach1, NSCD, and LaminB2 siRNAs had no effect on HO-2 or 5-aminolevulinate synthase-1 mRNA levels (two genes that are not induced by heme). The effects of increasing concentrations of heme (up to 10 μM) in the presence or absence of Bach1-siRNA on the levels of HO-1 mRNA expression are shown in the Figure. For all of the heme concentrations tested, the levels of HO-1 mRNA were greater when Bach1 siRNA was present. Conclusions: Bach1 has a specific and selective effect to repress expression of human hepatic HO-1. Silencing of the Bach1 gene by siRNAs may be a useful method for up-regulating HO-1 gene expression. The combination of intravenous heme and Bach1 silencing may be useful for therapy of acute porphyrias in relapse or other conditions in which up-regulation of HO-1 may be beneficial. (Supported by grants from NIH [DK38825] and Ovation Pharmaceuticals, Inc.) Figure Figure

Heme Oxygenase 1 Plays An Unexpected Role During Erythroid Differentiation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 344-344
Author(s):  
Daniel Garcia Santos ◽  
Matthias Schranzhofer ◽  
José Artur Bogo Chies ◽  
Prem Ponka
Keyword(s):  
Red Blood Cells ◽  
Heme Oxygenase ◽  
Blood Cells ◽  
Erythroid Differentiation ◽  
Heme Biosynthesis ◽  
Erythroid Cell ◽  
Heme Oxygenase 1 ◽  
Erythroid Cells ◽  
Wild Type ◽  
Protein Levels

Abstract Abstract 344 Red blood cells (RBC) are produced at a rate of 2.3 × 106 cells per second by a dynamic and exquisitely regulated process known as erythropoiesis. During this development, RBC precursors synthesize the highest amounts of total organismal heme (75–80%), which is a complex of iron with protoporphyrin IX. Heme is essential for the function of all aerobic cells, but if left unbound to protein, it can promote free radical formation and peroxidation reactions leading to cell damage and tissue injury. Therefore, in order to prevent the accumulation of ‘free' heme, it is imperative that cells maintain a balance of heme biosynthesis and catabolism. Physiologically, the only enzyme capable of degrading heme are heme oxyganase 1 & 2 (HO). Red blood cells contain the majority of heme destined for catabolism; this process takes place in splenic and hepatic macrophages following erythrophagocytosis of senescent RBC. Heme oxygenase, in particular its heme-inducible isoform HO1, has been extensively studied in hepatocytes and many other non-erythroid cells. In contrast, virtually nothing is known about the expression of HO1 in developing RBC. Likewise, it is unknown whether HO1 plays any role in erythroid cell development under physiological or pathophysiological conditions. Using primary erythroid cells isolated from mouse fetal livers (FL), we have shown that HO1 mRNA and protein are expressed in undifferenetiated FL cells and that its levels, somewhat surprisingly, increase during erythropoietin-induced erythroid differentiation. This increase in HO1 can be prevented by succinylacetone (SA), an inhibitor of heme synthesis that blocks 5-aminolevulinic acid dehydratase, the second enzyme in the heme biosynthesis pathway. Moreover, we have found that down-regulation of HO1 via siRNA increases globin protein levels in DMSO-induced murine erythroleukemic (MEL) cells. Similarly, compared to wild type mice, FL cells isolated from HO1 knockout mice (FL/HO1−/−) exhibited increased globin and transferrin receptor levels and a decrease in ferritin levels when induced for differentiation with erythropoietin. Following induction, compared to wild type cells, FL/HO1−/− cells showed increased iron uptake and its incorporation into heme. We therefore conclude that the normal hemoglobinization rate appears to require HO1. On the other hand, MEL cells engineered to overexpress HO1 displayed reduced globin mRNA and protein levels when induced to differentiate. This finding suggests that HO1 could play a role in some pathophysiological conditions such as unbalanced globin synthesis in thalassemias. Disclosures: No relevant conflicts of interest to declare.

scholarly journals HEME OXYGENASE-1 GENE THERAPY FOR PREVENTION OF VASOSPASM IN RATS

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 330-330
Author(s):  
Robert L Macdonald Dr. ◽  
Shigeki Ono Dr.
Keyword(s):  
Blood Flow ◽  
Heme Oxygenase ◽  
Basilar Artery ◽  
Cerebral Arteries ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Messenger Ribonucleic Acid ◽  
Cisterna Magna ◽  
Protein Levels ◽  
Vehicle Injection

78 This study tested the hypothesis that adenovirus expressing heme oxygenase-1 (HO-1), the enzyme that metabolises hemoglobin, would reduce contractions of cerebral arteries to hemoglobin and decrease vasospasm after subarachnoid hemorrhage (SAH). Rats underwent injection of vehicle or replication defective adenovirus expressing HO-1 (Ad5HO-1) or β-galactosidase (Ad-βGal) into the cisterna magna. Transgene expression was assessed by reverse transcriptase polymerase chain reaction for messenger ribonucleic acid (mRNA) levels, immunoblotting for protein levels, immunohistochemistry, response of the basilar artery to pure, ferrous hemoglobin and carboxyhemoglobin production 1 day after virus injection. Effects of Ad5HO-1 and Ad-βGal on vasospasm were assessed in a rat double hemorrhage model. Injection of Ad5HO-1 significantly increased HO-1 mRNA, protein and activity in basilar artery compared to Ad-βGal and vehicle. Injection of Ad-βGal result in low level expression and activity of HO-1 but this was significantly less than after injection of Ad5HO-1. HO-1 immunoreactivity was present in the basilar artery adventitia after injection of Ad5HO-1 and Ad-βGal. Injection of Ad5HO-1 and Ad-βGal increased basilar artery diameter and brainstem blood flow compared to control (P < 0.001, ANOVA). Ad5HO-1, however, significantly and selectively prevented contraction of the basilar artery and reduction in brainstem cerebral blood flow due to hemoglobin and significantly increased carboxyhemoglobin concentration compared to Ad-βGal and vehicle. Basilar artery diameter 7 days after SAH was significantly greater after injection of Ad5HO-1 (380 ± 36 μm) compared to Ad-βGal (282 ± 44 μm) and vehicle (287 ± 31μm, P < 0.001, ANOVA). In conclusion, injection of Ad5HO-1 into the cisterna magna of rats results in expression of functional HO-1 in the adventitia of the basilar artery. This is associated with an increase in basilar artery diameter. HO-1 expression with Ad5HO-1 inhibits arterial contractions to hemoglobin and after SAH.

scholarly journals Surfactant protein A reduces TLR4 and inflammatory cytokine mRNA levels in neonatal mouse ileum

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lidan Liu ◽  
Chaim Z. Aron ◽  
Cullen M. Grable ◽  
Adrian Robles ◽  
Xiangli Liu ◽  
...  
Keyword(s):  
Proinflammatory Cytokine ◽  
Inflammatory Cytokine ◽  
Protein A ◽  
Surfactant Protein ◽  
Surfactant Protein A ◽  
Mrna Levels ◽  
Wild Type ◽  
Cytokine Mrna ◽  
Protein Levels ◽  
Cytokine Levels

AbstractLevels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A−/−) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A−/− mice compared to wild type mice. Gavage of neonatal SP-A−/− mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A−/− mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.

Starvation promotes Dictyostelium development by relieving PufA inhibition of PKA translation through the YakA kinase pathway

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3263-3274 ◽  
Author(s):  
G.M. Souza ◽  
A.M. da Silva ◽  
A. Kuspa
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Mrna Levels ◽  
Wild Type ◽  
Mobility Shift ◽  
Developmental Defects ◽  
C Protein ◽  
Protein Levels ◽  
Cell Extracts ◽  
Puf Protein

When nutrients are depleted, Dictyostelium cells undergo cell cycle arrest and initiate a developmental program that ensures survival. The YakA protein kinase governs this transition by regulating the cell cycle, repressing growth-phase genes and inducing developmental genes. YakA mutants have a shortened cell cycle and do not initiate development. A suppressor of yakA that reverses most of the developmental defects of yakA- cells, but none of their growth defects was identified. The inactivated gene, pufA, encodes a member of the Puf protein family of translational regulators. Upon starvation, pufA- cells develop precociously and overexpress developmentally important proteins, including the catalytic subunit of cAMP-dependent protein kinase, PKA-C. Gel mobility-shift assays using a 200-base segment of PKA-C's mRNA as a probe reveals a complex with wild-type cell extracts, but not with pufA- cell extracts, suggesting the presence of a potential PufA recognition element in the PKA-C mRNA. PKA-C protein levels are low at the times of development when this complex is detectable, whereas when the complex is undetectable PKA-C levels are high. There is also an inverse relationship between PufA and PKA-C protein levels at all times of development in every mutant tested. Furthermore, expression of the putative PufA recognition elements in wild-type cells causes precocious aggregation and PKA-C overexpression, phenocopying a pufA mutation. Finally, YakA function is required for the decline of PufA protein and mRNA levels in the first 4 hours of development. We propose that PufA is a translational regulator that directly controls PKA-C synthesis and that YakA regulates the initiation of development by inhibiting the expression of PufA. Our work also suggests that Puf protein translational regulation evolved prior to the radiation of metazoan species.

Adenoviral E3-14.7K protein in LPS-induced lung inflammation

2000 ◽  
Vol 278 (4) ◽  
pp. L631-L639 ◽  
Author(s):  
Kevin S. Harrod ◽  
Amber D. Mounday ◽  
Jeffrey A. Whitsett
Keyword(s):  
Transgenic Mice ◽  
Lung Inflammation ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Respiratory Epithelium ◽  
Wild Type ◽  
Intracellular Staining ◽  
Intratracheal Administration ◽  
Tnf Α

The adenoviral E3-14.7K protein is a cytoplasmic protein synthesized after adenoviral infection. To assess the contribution of E3-14.7K-sensitive pathways in the modulation of inflammation by the respiratory epithelium, inflammatory responses to intratracheal lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α were assessed in transgenic mice bearing the adenoviral E3-14.7K gene under the direction of the surfactant protein (SP) C promoter. When E3-14.7K transgenic mice were administered LPS intratracheally, lung inflammation as indicated by macrophage and neutrophil accumulation in bronchoalveolar lavage fluid was decreased compared with wild-type control mice. Lung inflammation and epithelial cell injury were decreased in E3-14.7K mice 24 and 48 h after LPS administration. Intracellular staining for surfactant proprotein (proSP) B, proSP-C, and SP-B was decreased and extracellular staining was markedly increased in wild-type mice after LPS administration, consistent with LPS-induced lung injury. In contrast, intense intracellular staining of proSP-B, proSP-C, and SP-B persisted in type II cells of E3-14.7K mice, whereas extracellular staining of proSP-B and proSP-C was absent. Inhibitory effects of intratracheal LPS on SP-C mRNA were ameliorated by expression of the E3-14.7Kgene. Similar to the response to LPS, lung inflammation after intratracheal administration of TNF-α was decreased in E3-14.7K transgenic mice. Levels of TNF-α after LPS administration were similar in wild-type and E3-14.7K-bearing mice. Cell-selective expression of E3-14.7K in the respiratory epithelium inhibited LPS- and TNF-α-mediated lung inflammation, demonstrating the critical role of respiratory epithelial cells in LPS- and TNF-α-induced lung inflammation.

Enhancement of DEN-induced liver tumorigenesis in heme oxygenase-1 G143H mutant transgenic mice

2016 ◽  
Vol 481 (1-2) ◽  
pp. 169-175 ◽  
Author(s):  
Jianfeng Jin ◽  
Dayong Wang ◽  
Haifeng Xiao ◽  
Huiyan Wei ◽  
Cedric Matunda ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1

Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse β-cells

2007 ◽  
Vol 293 (3) ◽  
pp. E645-E655 ◽  
Author(s):  
Subbiah Pugazhenthi ◽  
Leonid Akhov ◽  
Gopalan Selvaraj ◽  
Maorong Wang ◽  
Jawed Alam
Keyword(s):  
Signaling Pathways ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Regulatory Subunit ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Phase 2 ◽  
Β Cells

Curcumin (diferuloylmethane), a component of turmeric, has been shown to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, has been reported to have cytoprotective effects in pancreatic β-cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse β-cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response element (ARE) sites containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of nuclear factor-E2-related factor (Nrf2), the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific signaling pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of phosphotidylinositol 3-kinase and Akt. Real-time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase, which is needed for the synthesis of glutathione, and NAD(P)H:quinone oxidoreductase, which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in β-cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in β-cells under conditions of stress as seen in diabetes.

scholarly journals Hmox1 (Heme Oxygenase-1) Protects Against Ischemia-Mediated Injury via Stabilization of HIF-1α (Hypoxia-Inducible Factor-1α)

2020 ◽  
Author(s):  
Louise L. Dunn ◽  
Stephanie M.Y. Kong ◽  
Sergey Tumanov ◽  
Weiyu Chen ◽  
James Cantley ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Carbon Monoxide ◽  
Blood Flow ◽  
Heme Oxygenase ◽  
Hypoxia Inducible Factor ◽  
Ischemic Injury ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Tissue Necrosis ◽  
Hypoxia Inducible Factor 1Α

Objective: Hmox1 (heme oxygenase-1) is a stress-induced enzyme that catalyzes the degradation of heme to carbon monoxide, iron, and biliverdin. Induction of Hmox1 and its products protect against cardiovascular disease, including ischemic injury. Hmox1 is also a downstream target of the transcription factor HIF-1α (hypoxia-inducible factor-1α), a key regulator of the body’s response to hypoxia. However, the mechanisms by which Hmox1 confers protection against ischemia-mediated injury remain to be fully understood. Approach and Results: Hmox1 deficient ( Hmox1 –/– ) mice had impaired blood flow recovery with severe tissue necrosis and autoamputation following unilateral hindlimb ischemia. Autoamputation preceded the return of blood flow, and bone marrow transfer from littermate wild-type mice failed to prevent tissue injury and autoamputation. In wild-type mice, ischemia-induced expression of Hmox1 in skeletal muscle occurred before stabilization of HIF-1α. Moreover, HIF-1α stabilization and glucose utilization were impaired in Hmox1 –/– mice compared with wild-type mice. Experiments exposing dermal fibroblasts to hypoxia (1% O 2 ) recapitulated these key findings. Metabolomics analyses indicated a failure of Hmox1 –/– mice to adapt cellular energy reprogramming in response to ischemia. Prolyl-4-hydroxylase inhibition stabilized HIF-1α in Hmox1 –/– fibroblasts and ischemic skeletal muscle, decreased tissue necrosis and autoamputation, and restored cellular metabolism to that of wild-type mice. Mechanistic studies showed that carbon monoxide stabilized HIF-1α in Hmox1 –/– fibroblasts in response to hypoxia. Conclusions: Our findings suggest that Hmox1 acts both downstream and upstream of HIF-1α, and that stabilization of HIF-1α contributes to Hmox1’s protection against ischemic injury independent of neovascularization.

Heme oxygenase expression and Nrf2 signaling during hibernation in ground squirrelsThis article is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.

2010 ◽  
Vol 88 (3) ◽  
pp. 379-387 ◽  
Author(s):  
Zhouli Ni ◽  
Kenneth B. Storey
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Muscle Power ◽  
Ground Squirrels ◽  
Heme Oxygenase 1 ◽  
Antioxidant Defences ◽  
Protein Levels ◽  
Brown Adipose ◽  
Distribution Studies

Mammalian hibernation is composed of long periods of deep torpor interspersed with brief periods of arousal in which the animals, fueled by high rates of oxygen-based thermogenesis in brown adipose tissue and skeletal muscle, power themselves back to euthermic (~37 °C) body temperatures. Strong antioxidant defences are important both for long-term cytoprotection during torpor and for coping with high rates of reactive oxygen species generated during arousal. The present study shows that the antioxidant enzyme heme oxygenase 1 (HO1) is strongly upregulated in selected organs of thirteen-lined ground squirrels (Spermophilus tridecemlineatus) during hibernation. Compared with euthermic controls, HO1 mRNA transcript levels were 1.4- to 3.8-fold higher in 5 organs of hibernating squirrels, whereas levels of the constitutive isozyme HO2 were unchanged. Similarly, HO1 protein levels increased by 1.5- to 2.0-fold in liver, kidney, heart, and brain during torpor. Strong increases in the levels of the Nrf2 transcription factor and its heterodimeric partner protein, MafG, in several tissues indicated the mechanism of activation of hibernation-responsive HO1 gene expression. Furthermore, subcellular distribution studies with liver showed increased nuclear translocation of both Nrf2 and MafG in torpid animals. The data are consistent with the suggestion that Nrf2-mediated upregulation of HO1 expression provides enhanced antioxidant defence to counter oxidative stress in hibernating squirrels during torpor and (or) arousal.

Sign in / Sign up

Export Citation Format

Share Document