Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on heme oxygenase-1, biliverdin IXα reductase and δ-aminolevulinic acid synthetase 1 in rats with wild-type or variant AH receptor

Toxicology ◽  
2008 ◽  
Vol 250 (2-3) ◽  
pp. 132-142 ◽  
Author(s):  
Marjo Niittynen ◽  
Jouni T. Tuomisto ◽  
Raimo Pohjanvirta
Keyword(s):  
Heme Oxygenase ◽  
Aminolevulinic Acid ◽  
Ah Receptor ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Tetrachlorodibenzo P Dioxin

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.

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 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.

5-Aminolevulinic acid combined with ferrous iron enhances the expression of heme oxygenase-1

2014 ◽  
Vol 19 (2) ◽  
pp. 300-307 ◽  
Author(s):  
Yoshiaki Nishio ◽  
Masayuki Fujino ◽  
Mingyi Zhao ◽  
Takuya Ishii ◽  
Masahiro Ishizuka ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Ferrous Iron ◽  
Aminolevulinic Acid ◽  
Heme Oxygenase 1

Role of heme oxygenase-1 in the cardioprotective effects of erythropoietin during myocardial ischemia and reperfusion

2009 ◽  
Vol 296 (1) ◽  
pp. H84-H93 ◽  
Author(s):  
Dylan Burger ◽  
Fuli Xiang ◽  
Lamis Hammoud ◽  
Xiangru Lu ◽  
Qingping Feng
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Heme Oxygenase ◽  
Ischemia Reperfusion ◽  
Primary Cultures ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Myocardial Ischemia And Reperfusion ◽  
Cardioprotective Effects

We have recently demonstrated that erythropoietin (EPO) protects cardiomyocytes from apoptosis during myocardial ischemia-reperfusion (I/R). The objective of the present study was to investigate the role of heme oxygenase (HO)-1 in the antiapoptotic effects of EPO. Primary cultures of neonatal mouse cardiomyocytes were subjected to anoxia-reoxygenation (A/R). Pretreatment with EPO significantly reduced apoptosis in A/R-treated cells. This reduction in apoptosis was preceded by an increase in the mRNA and protein expression of HO-1. Selective inhibition of HO-1 using chromium mesoporphyrin (CrMP) significantly diminished the ability of EPO to inhibit apoptosis. Cotreatment of EPO with SB-202190, an inhibitor of p38 activation, blocked the EPO-mediated HO-1 expression and antiapoptotic effects, suggesting a p38-dependent mechanism. The in vivo significance of p38 and HO-1 as mediators of EPO's cardioprotection was investigated in mice subjected to myocardial I/R. Pretreatment with EPO decreased infarct size as well as I/R-induced apoptosis in wild-type mice. However, these effects were significantly diminished in HO-1−/−mice. Furthermore, EPO given during ischemia reduced infarct size in mice subjected to I/R, and this effect was blocked by CrMP treatment in wild-type mice. Moreover, inhibition of p38 diminished the cardioprotective effects of EPO. We conclude that upregulation of HO-1 expression via p38 signaling contributes to EPO-mediated cardioprotection during myocardial I/R.

scholarly journals Heme oxygenase-1-dependent central cardiorespiratory adaptations to chronic hypoxia in mice

2009 ◽  
Vol 297 (2) ◽  
pp. R300-R312 ◽  
Author(s):  
Jagadeeshan Sunderram ◽  
John Semmlow ◽  
Smita Thakker-Varia ◽  
Mantu Bhaumik ◽  
Oanh Hoang-Le ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Sympathetic Activity ◽  
Time Course ◽  
Chronic Hypoxia ◽  
Acute Hypoxia ◽  
Ventrolateral Medulla ◽  
Heme Oxygenase 1 ◽  
Respiratory Response ◽  
Wild Type ◽  
Sympathetic Responses

Adaptations to chronic hypoxia (CH) could reflect cellular changes within the cardiorespiratory regions of the rostral ventrolateral medulla (RVLM), the C1 region, and the pre-Bötzinger complex (pre-BötC). Previous studies have shown that the hypoxic chemosensitivity of these regions are heme oxygenase (HO) dependent and that CH induces HO-1. To determine the time course of HO-1 induction within these regions and explore its relevance to the respiratory and sympathetic responses during CH, the expression of HO-1 mRNA and protein in the RVLM and measures of respiration, sigh frequency, and sympathetic activity (spectral analysis of heart rate) were examined during 10 days of CH. Respiratory and sympathetic responses to acute hypoxia were obtained in chronically instrumented awake wild-type (WT) and HO-1 null mice. After 4 days of CH, there was a significant induction of HO-1 within the C1 region and pre-BötC. WT mice acclimated to CH by increasing peak diaphragm EMG after 10 days of CH but had no change in the respiratory response to acute hypoxia. There were no significant differences between WT and HO-1 null mice. In WT mice, hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity initially declined before returning toward baseline after 5 days of CH, correlating with the induction of HO-1. In contrast, HO-1 null mice had a persistent decline in hypoxic sigh frequency and hypoxic sensitivity of sympathetic activity. We conclude that induction of HO-1 in these RVLM cardiorespiratory regions may be important for the hypoxic sensitivity of sighs and sympathetic activity during CH.

scholarly journals Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Kazushige Ota ◽  
Andrey Brydun ◽  
Ari Itoh-Nakadai ◽  
Jiying Sun ◽  
Kazuhiko Igarashi
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Heme Oxygenase ◽  
Transcriptional Activity ◽  
Oxidative Stress Response ◽  
Acute Injury ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Environmental Perturbations ◽  
Deficient Mice

Oxidative stress contributes to both aging and tumorigenesis. The transcription factor Bach1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1) gene (Hmox1) and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects ofBach1deficiency on mice.Bach1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells ofBach1-deficient animals, the levels of ROS inBach1-deficient HSCs were comparable to those in wild-type cells.Bach1−/−;p53−/−mice succumbed to spontaneous cancers as frequently asp53-deficient mice.Bach1deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation toBach1deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded thatBach1deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target Bach1 for acute injury responses without inducing any apparent deteriorative effect.

Impaired synthesis of heme oxygenase-1 in Fanconi anemia cells can be rescued by transfection of Fanconi wild-type cDNA

2008 ◽  
Vol 389 (10) ◽  
Author(s):  
Maria Kontou ◽  
Monica Hirsch-Kauffmann ◽  
Manfred Schweiger
Keyword(s):  
Heme Oxygenase ◽  
Fanconi Anemia ◽  
Alkylating Agents ◽  
Chromosome Instability ◽  
Heme Oxygenase 1 ◽  
Oxygen Sensitivity ◽  
Wild Type ◽  
Oxygen Intermediates ◽  
Defense Protein ◽  
Progressive Pancytopenia

AbstractFanconi anemia is a fatal, hereditary chromosome instability syndrome of early childhood with progressive pancytopenia and cancer-proneness. Hypersensitivity to alkylating agents points to DNA repair inefficiency. Excess reactive oxygen intermediates and hypersensitivity to oxygen, all features of Fanconi anemia cells, give evidence for a disturbed oxidative metabolism. Here, we report that expression of the inducible heme oxygenase-1, an essential antioxidative defense protein, is impaired in Fanconi anemia cells and can be reinstated with the transfection of Fanconi A wild-type cDNA. A causative interaction of Fanconi anemia proteins with transcription of selected proteins is indicated. The results enlighten the oxygen sensitivity in Fanconi anemia.

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