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.

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.

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Heme Oxygenase 1 Impairs Glucocorticoid Receptor Activity in Prostate Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20051006 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1006 ◽

Cited By ~ 5

Author(s):

Daiana Leonardi ◽

Nicolás Anselmino ◽

Javier Brandani ◽

Felipe Jaworski ◽

Alejandra Páez ◽

...

Keyword(s):

Prostate Cancer ◽

Glucocorticoid Receptor ◽

Western Blot ◽

Heme Oxygenase ◽

Nuclear Translocation ◽

Heme Oxygenase 1 ◽

Castration Resistant Prostate Cancer ◽

Protein Levels ◽

Pre Treatment

Glucocorticoids are used during prostate cancer (PCa) treatment. However, they may also have the potential to drive castration resistant prostate cancer (CRPC) growth via the glucocorticoid receptor (GR). Given the association between inflammation and PCa, and the anti-inflammatory role of heme oxygenase 1 (HO-1), we aimed at identifying the molecular processes governed by the interaction between HO-1 and GR. PCa-derived cell lines were treated with Hemin, Dexamethasone (Dex), or both. We studied GR gene expression by RTqPCR, protein expression by Western Blot, transcriptional activity using reporter assays, and nuclear translocation by confocal microscopy. We also evaluated the expression of HO-1, FKBP51, and FKBP52 by Western Blot. Hemin pre-treatment reduced Dex-induced GR activity in PC3 cells. Protein levels of FKBP51, a cytoplasmic GR-binding immunophilin, were significantly increased in Hemin+Dex treated cells, possibly accounting for lower GR activity. We also evaluated these treatments in vivo using PC3 tumors growing as xenografts. We found non-significant differences in tumor growth among treatments. Immunohistochemistry analyses revealed strong nuclear GR staining in almost all groups. We did not observe HO-1 staining in tumor cells, but high HO-1 reactivity was detected in tumor infiltrating macrophages. Our results suggest an association and crossed modulation between HO-1 and GR pathways.

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The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms20102427 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2427 ◽

Cited By ~ 8

Author(s):

Maayan Waldman ◽

Vadim Nudelman ◽

Asher Shainberg ◽

Romy Zemel ◽

Ran Kornwoski ◽

...

Keyword(s):

Oxidative Stress ◽

Beneficial Effect ◽

Heme Oxygenase ◽

Diabetic Cardiomyopathy ◽

High Glucose ◽

Heme Oxygenase 1 ◽

Ros Production ◽

Diabetic Mice ◽

Protein Levels

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1–PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. Methods: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5–33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. Results: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. Conclusion: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.

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Deletion ofHerpud1Enhances Heme Oxygenase-1 Expression in a Mouse Model of Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2016/6163934 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Thuong Manh Le ◽

Koji Hashida ◽

Hieu Minh Ta ◽

Mika Takarada-Iemata ◽

Koichi Kokame ◽

...

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Heme Oxygenase ◽

Active Form ◽

Heme Oxygenase 1 ◽

Protein Levels ◽

The Status ◽

Mptp Administration

Herp is an endoplasmic reticulum- (ER-) resident membrane protein that plays a role in ER-associated degradation. We studied the expression of Herp and its effect on neurodegeneration in a mouse model of Parkinson’s disease (PD), in which both the oxidative stress and the ER stress are evoked. Eight hours after administering a PD-related neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to mice, the expression of Herp increased at both the mRNA and the protein levels. Experiments usingHerpud1+/+andHerpud1−/−mice revealed that the status of acute degeneration of nigrostriatal neurons and reactive astrogliosis was comparable between two genotypes after MPTP injection. However, the expression of a potent antioxidant, heme oxygenase-1 (HO-1), was detected to a higher degree in the astrocytes ofHerpud1−/−mice than in the astrocytes ofHerpud1+/+mice 24 h after MPTP administration. Further experiments using cultured astrocytes revealed that the stress response against MPP+, an active form of MPTP, and hydrogen peroxide, both of which cause oxidative stress, was comparable between the two genotypes. These results suggest that deletion ofHerpud1may cause a slightly higher level of initial damage in the nigrastrial neurons after MPTP administration but is compensated for by higher induction of antioxidants such as HO-1 in astrocytes.

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Wood smoke extract induces oxidative stress-mediated caspase-independent apoptosis in human lung endothelial cells: role of AIF and EndoG

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00099.2005 ◽

2005 ◽

Vol 289 (5) ◽

pp. L739-L749 ◽

Cited By ~ 69

Author(s):

Po-Len Liu ◽

Yuh-Lien Chen ◽

Yung-Hsiang Chen ◽

Shing-Jong Lin ◽

Yu Ru Kou

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Superoxide Dismutase ◽

Antioxidant Enzymes ◽

Dna Fragmentation ◽

Heme Oxygenase ◽

Nuclear Translocation ◽

Wood Smoke ◽

Heme Oxygenase 1 ◽

Lung Endothelial Cells

Although a link between toxic smoke and oxidant lung vascular injury has been indicated, the cellular mechanisms of smoke-induced injury to lung endothelial cells are unknown. We investigated oxidative stress and apoptosis induced by wood smoke extract (SE) in human pulmonary artery endothelial cells (HPAECs) and delineated their relationship. We found that SE increased intracellular reactive oxygen species (ROS), depleted intracellular glutathione, and upregulated Cu/Zn superoxide dismutase and heme oxygenase-1 (2 antioxidant enzymes), but it failed to alter the expression of catalase and glutathione peroxidase. In addition, SE promoted apoptosis as indicated by the external exposure of membrane phosphatidylserine, the loss of mitochondrial membrane potential, an increase in the level of Bax (a proapoptotic protein), and enhanced DNA fragmentation. This apoptosis was associated with mitochondrial-to-nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) (2 apoptogenic proteins) but was independent of caspase cascade activation. Whereas N-acetylcysteine (an antioxidant) effectively reversed the SE-induced increase in ROS and depletion of glutathione, it also suppressed SE-induced nuclear translocation of either AIF or EndoG and prevented the enhanced DNA fragmentation that would have resulted from this. We conclude that 1) although SE upregulates Cu/Zn superoxide dismutase and heme oxygenase-1, it nevertheless increases intracellular oxidative stress in HPAECs, and 2) SE promotes oxidative stress-mediated caspase-independent HPAEC apoptosis that involves mitochondrial-to-nuclear translocation of AIF and EndoG. Thus modulations of the expression of antioxidant enzymes and the caspase-independent apoptotic pathway are possible target choices for potential therapeutic regimes to treat smoke-induced lung injury.

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Inhibitory Effect of Delphinidin on Oxidative Stress Induced by H2O2 in HepG2 Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4694760 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Jingjing Xu ◽

Yanwei Zhang ◽

Guofeng Ren ◽

Rengui Yang ◽

Jingfang Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Hepg2 Cells ◽

Nuclear Translocation ◽

Inhibitory Effect ◽

Scientific Data ◽

Liver Carcinoma ◽

Heme Oxygenase 1 ◽

Protein Levels ◽

Intracellular Ros ◽

Nrf2 Protein

Chronic liver diseases (CLDs) are correlated with oxidative stress induced by the accumulation of intracellular reactive oxygen species (ROS). In this study, we employed HepG2, a human liver carcinoma cell line containing many antioxidant enzymes, to explore the function of delphinidin against oxidative stress induced by H2O2 and to provide scientific data of the molecular mechanism. Cells were pretreated with different concentrations of delphinidin (10 μmol/L, 20 μmol/L, and 40 μmol/L) for 2 h before treatment with 750 μM H2O2 for 1 h. The results showed that H2O2 decreased the survival rate of HepG2 cells and increased the level of ROS, but delphinidin pretreatment could possess the opposite result. At the same time, the expression of Nrf2 was enhanced by the delphinidin pretreatment. This was because delphinidin promoted Nrf2 nuclear translocation and inhibited its degradation, which led to the increase expression of antioxidant protein HO-1 (Nrf2-related phase II enzyme heme oxygenase-1). Besides, we found that delphinidin could significantly alleviate the reduction of Nrf2 protein levels and the accumulation of intracellular ROS levels in Nrf2 knockdown HepG2 cells. In conclusion, our study suggested that delphinidin, as an effective antioxidant, protected HepG2 cells from oxidative stress by regulating the expression of Nrf2/HO-1.

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Lablab purpureus Protects HaCaT Cells from Oxidative Stress-Induced Cell Death through Nrf2-Mediated Heme Oxygenase-1 Expression via the Activation of p38 and ERK1/2

International Journal of Molecular Sciences ◽

10.3390/ijms21228583 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8583

Author(s):

Nurud Diniyah ◽

Md Badrul Alam ◽

Hee-Jeong Choi ◽

Sang-Han Lee

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

High Performance ◽

Nuclear Translocation ◽

Antioxidant Activities ◽

Ethanolic Extract ◽

Ultraviolet B ◽

Heme Oxygenase 1 ◽

Hacat Cells ◽

Lablab Purpureus

Ultraviolet B (UV-B) radiation induces the extreme production of either reactive oxygen species (ROS) or inflammatory mediators. The aim of this study was to evaluate the antioxidant activities of 70% ethanolic extract of Lablab purpureus (LPE) and the underlying mechanisms using HaCaT cells exposed to UV-B. High-performance liquid chromatography (HPLC) confirmed the presence of gallic acid, catechin, and epicatechin in LPE. LPE was shown to have a very potent capacity to scavenge free radicals. The results showed that LPE prevented DNA damage and inhibited the generation of ROS in HaCaT cells without causing any toxicity. LPE increased the expression of endogenous antioxidant enzymes such as superoxide dismutase-1 and catalase. Furthermore, LPE treatment facilitates the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), boosting the phase II detoxifying enzyme heme oxygenase-1 (HO-1) leading to the combatting of oxidative stress. However, pretreatment of LPE also caused the phosphorylation of mitogen-activated protein kinases (MAPK kinase) (p38 kinase) and extracellular signal-regulated kinase (ERK), whereas treatment with p38 and ERK inhibitors substantially suppressed LPE-induced Nrf2 and heme oxygenase (HO)-1 expression. These findings suggest that LPE exhibits antioxidant activity via Nrf-2-mediated HO-1 signaling through the activation of p38 and ERK, indicating that LPE can potentially be used as a remedy to combat oxidative stress-induced disorder.

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Faculty Opinions recommendation of Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1089363.542588 ◽

2007 ◽

Author(s):

William Welch

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Heme Oxygenase ◽

Heme Oxygenase 1

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Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms22041514 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1514 ◽

Cited By ~ 1

Author(s):

Akihiro Yachie

Keyword(s):

Oxidative Stress ◽

Animal Models ◽

Heme Oxygenase ◽

Inflammatory Diseases ◽

Cell Types ◽

Pharmacological Intervention ◽

Heme Oxygenase 1 ◽

Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

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Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

International Journal of Molecular Sciences ◽

10.3390/ijms22158253 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8253

Author(s):

Jung-Yeon Kim ◽

Yongmin Choi ◽

Jaechan Leem ◽

Jeong Eun Song

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Heme Oxygenase ◽

Murine Model ◽

Liver Diseases ◽

Transforming Growth Factor ◽

Heme Oxygenase 1 ◽

Cholestatic Liver Disease ◽

Hepatocyte Apoptosis ◽

Cobalt Protoporphyrin

Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.

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