Flowchart: Preparation: HO-1

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Text Box: Acrolein
 

 

 


Text Box: Nrf2                                 

                                                

Text Box: H0-1                                                                                                

 

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Text Box: ApotosisText Box: Vegf                                                                                                                   

                                                                 

 

                                                                               

 

Text Box: Carbon Monoside(CO)
 

 

 


     

 

Text Box: PC12 cell
 


                                                

 

 

 

 

 

 

 

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2006 Jan;24(1):16-9.

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[Heme oxygenase-1 expression and apoptosis induced by cadmium in human embryon kidney cells]

[Article in Chinese]

Chang XL, Jin TY, Chen L, Dong C.

Department of Occupation Health,
Public Health School of Fudan University, Shanghai 200032, China.

OBJECTIVE: To investigate apoptosis and expression of heme oxygenase-1 (HO-1) induced by cadmium in human embryonic kidney cells (HEK239T). METHODS: The MTT method was used for determining the cell proliferation activity. The apoptosis was determined by the flow cytometry. The HO-l mRNA expression and protein level were detected by RT-PCR method and Western blot respectively. RESULTS: The ratios of apoptosis in HEK239T cells were 11.90% +/- 0.28%, 9.27% +/- 1.73%, 9.79% +/- 0.67% and 8 .97% +/- 1.60% at the concentration of 5.0, 10.0, 20.0 and 40.0 micromol/L CdCl(2) respectively, higher than those in the control group (6.69% +/- 0.46%) with the significant difference (P < 0.01). The CdCl(2) of between 10 and 40 micromol/L could highly induce the expression of HO-1 of the human embryonic kidney cells. The expression would increase slowly till the flat stage with the increase of the dosage and then would decrease slightly over time. CONCLUSION: The cadmium can induce the apoptosis of the human embryonic kidney cells and up-regulate the expression of HO-1.

PMID: 16600087 [PubMed - in process]

Biochem Biophys Res Commun. 2006 Apr 14;342(3):984-90.

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Carbon monoxide protects PC12 cells from peroxynitrite-induced apoptotic death by preventing the depolarization of mitochondrial transmembrane potential.

Li MH, Cha YN, Surh YJ.

Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in catalyzing heme degradation into biliverdin, free iron, and carbon monoxide (CO), serves as a protective enzyme against oxidative and nitrosative stresses. In the present study, we investigated the cytoprotective effects of HO-1 upregulation and its product CO against the peroxynitrite-induced PC12 cell death. PC12 cells treated with 3-morphoinosydonimine (SIN-1), a generator of peroxynitrite (ONOO-), underwent apoptotic cell death as evidenced by dissipation of mitochondrial transmembrane potential (DeltaPsim), release of mitochondrial cytochrome c into cytoplasm, cleavage of poly(ADP-ribose)polymerase and fragmentation of internucleosomal DNA. Pretreatment of PC12 cells with a low non-toxic concentration of SIN-1 (0.5 mM) induced HO-1 expression and abrogated the cell death caused by subsequent challenge with high dose SIN-1 (2.5 mM). Furthermore, pretreatment of PC12 cells with SnCl2, a potent inducer of HO-1 expression, increased endogenous production of CO (HO activity) and rescued the PC12 cells from peroxynitrite-induced apoptosis. The cytoprotective effect of SnCl2 was abolished when the HO activity was inhibited by zinc protoporphyrin IX (ZnPP IX). PC12 cells treated directly with the CO-releasing molecule, tricarbonyldichlororuthenium (II) dimer ([Ru(CO)3Cl2]2) became tolerant to the depolarization of DeltaPsim and apoptosis induced by high dose peroxynitrite. Taken together, these data demonstrate that the adaptive protection against peroxynitrite-induced apoptotic death in PC12 cells is mediated by CO formed as a consequence of HO-1 induction.

PMID: 16598857 [PubMed - in process]

J Pharmacol Exp Ther. 2006 Mar 24; [Epub ahead of print]

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Induction of heme oxygenase-1 is involved in CO mediated central cardiovascular regulation.

Lo WC, Lu PJ, Ho WY, Hsiao M, Tseng CJ.

Department of Medical Education and Research,
Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Carbon monoxide (CO) has been identified as an endogenous biological messenger in the brain. Heme oxygenase (HO) catalyzes the metabolism of heme to CO and biliverdin. Previously, we have shown the involvement of CO in central cardiovascular regulation, baroreflex modulation, and glutaminergic neurotransmission in the nucleus tractus solitarii (NTS) of rats. In this study, we examined which HO isoform could be induced after hemin injection in the NTS. We also investigated their in-situ distributions in the NTS after induction. Male Sprague-Dawley (SD) rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Unilateral microinjection of hemin (1 nmol), a heme molecule cleaved by HO to yield CO, produced significant decrease in blood pressure and heart rate. These cardiovascular effects of hemin were attenuated by prior administration of HO inhibitor zinc protoporphyrin IX (ZnPPIX). Microinjection of hemin into NTS resulted in significant induction of HO-1 protein expression in-situ. Pretreatment of ZnPPIX significantly inhibited the HO-1 induction after hemin injection. No significant changes of HO-2 expressions were found after hemin injection and ZnPPIX pretreatment. The in-situ inductions of the HO-1 protein expression were further confirmed to be in glial cells and neurons after hemin injections into the NTS. These results indicated HO-1 but not HO-2 might be responsible for the generation of CO and contribute to central control of cardiovascular effects.

 

Toxicol Appl Pharmacol. 2006 Feb 7; [Epub ahead of print]

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Upregulation of endothelial heme oxygenase-1 expression through the activation of the JNK pathway by sublethal concentrations of acrolein.

Wu CC, Hsieh CW, Lai PH, Lin JB, Liu YC, Wung BS.

Institute of Biotechnology, National Chiayi University, Chiayi, Taiwan.

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde that is present in cigarette smoke. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by various such electrophilic compounds. In this study, the regulatory effects of acrolein upon the expression of HO-1 were investigated in endothelial cells (ECs). We demonstrate that acrolein induces the elevation of HO-1 protein levels, and subsequent enzyme activity, at non-cytotoxic concentrations. An additional alpha,beta-unsaturated aldehyde, cinnamaldehyde, was also found to increase HO-1 expression and have less cytotoxicity than acrolein. Moreover, acrolein-mediated HO-1 induction is abrogated in the presence of actinomycin D and cycloheximide. Nrf2 is a transcription factor involved in the induction of HO-1 through an antioxidant response element (ARE) in the promoter region of the HO-1 gene. We show that acrolein induces Nrf2 translocation and ARE-luciferase reporter activity. Acrolein was also found to induce the production of both superoxide and H(2)O(2) at levels greater than 100 muM. However, with the exception of NAC, no antioxidant generated any effect upon acrolein-dependent HO-1 expression in ECs. Our present findings suggest that reactive oxygen species (ROS) may not be a major modulator for HO-1 induction. Using buthionine sulfoximine to deplete the intracellular GSH levels further enhanced the effects of acrolein. We also found that cellular GSH level was rapidly reduced after both 10 and 100 muM acrolein treatment. However, after 6 h of exposure to ECs, only 10 muM acrolein treatment increases GSH level. In addition, only the JNK inhibitor SP600125 and tyrosine kinase inhibitor genistein had any significant inhibitory impact upon the upregulation of HO-1 by acrolein. Pretreatment with a range of other PI3 kinase inhibitors, including wortmannin and LY294002, showed no effects. Hence, we show in our current experiments that a sublethal concentration of acrolein is in fact a novel HO-1 inducer, and we further identify the principal underlying mechanisms involved in this process.

PMID: 16480751 [PubMed - as supplied by publisher]


 

 

 

 

 

 

 

 

J Biol Chem. 2006 Apr 4; [Epub ahead of print]

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Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes.

Di Noia MA, Van Driesche S, Palmieri F, Yang LM, Quan S, Goodman AI, Abraham NG.

Pharmacology,
New York Medical College, Valhalla, NY 10595.

Upregulation of heme oxygenase (HO-1) by either cobalt protoporphyrin (CoPP) or human gene transfer improves vascular and renal function by several mechanisms, including increases in antioxidant levels and decreases in reactive oxygen species (ROS) in vascular and renal tissue. The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase and anti-apoptotic proteins in diabetic rats (streptozotocin, (STZ)-induced type 1). Renal mitochondrial carnitine, deoxynucleotide and ADP/ATP carriers were significantly reduced in diabetic compared to nondiabetic rats (p<0.05). The citrate carrier was not significantly decreased in diabetic tissue. CoPP administration produced a robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate and ADP/ATP carriers but no significant change in oxoglutarate and aspartate/glutamate carriers. The increase in mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity. The administration of tin mesoporphyrin (SnMP), an inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats. Human HO-1 gene transfer into diabetic rats increased both HO-1 protein and activity, and restored mitochondrial ADP/ATP and deoxynucleotide carriers. The increase in HO-1 by CoPP administration was associated with a significant increase in the phosphorylation of AKT and levels of BcL-XL proteins. These observations in experimental diabetes suggest that the cytoprotective mechanism of HO-1 against oxidative stress involves an increase in the levels of MCs and anti-apoptotic proteins as well as in cytochrome c oxidase activity.

PMID: 16595661 [PubMed - as supplied by publisher]

 

J Biol Chem. 2006 Mar 21; [Epub ahead of print]

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Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusionof the transcription factor NRF2.

Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A.

Dpto. Bioquimica and Instituto de Investigaciones Biomedicas, Universidad
Autonoma de Madrid, Madrid, Madrid 28029.

The transcription factor Nrf2 (Nuclear factor E2-related factor 2) regulates the expression of antioxidant phase II genes and contributes to preserve redox homeostasis and cell viability in response to oxidant insults. Nrf2 should be coordinated with the canonical cell survival pathway represented by phosphatidylinositol 3-kinase (PI3K) and the Ser/Thr kinase Akt but so far the mechanistic connections remain undefined. Here we identify glycogen synthase kinase-3beta (GSK-3beta), which is inhibited by Akt-mediated phosphorylation, as the link between both processes. Using heme oxygenase-1 (HO-1) as a model phase II gene, we found that both PI3K and Akt increased mRNA and protein levels of this enzyme. Pharmacological inhibitors (LiCl and PDZD-8) and genetic variants of GSK-3beta (constitutively active and dominant negative mutants) indicated that PI3K/Akt activates and GSK-3beta inhibits the Antioxidant Response Elements of the ho1 promoter and pointed Nrf2 as directly involved in this process. Indeed, GSK-3beta phosphorylated Nrf2 in vitro and in vivo. Immunocytochemistry and subcellular fractionation analyses demonstrated that the effect of GSK-3beta-mediated phosphorylation of Nrf2 is to exclude this transcription factor from the nucleus. Nrf2 up-regulated the expression of HO-1, glutathione peroxidase, glutathione S transferase A1, NAD(P)H: quinone oxidoreductase and glutamate-cysteine ligase and protected against hydrogen peroxide-induced glutathione depletion and cell death, while co-expression of active GSK-3beta attenuated both phase II gene expression and oxidant protection. These results contribute to clarify the crosstalk between the survival signal elicited by PI3K/Akt and the antioxidant phase II cell response, and introduce GSK-3beta as the key mediator of this regulation mechanism.

PMID: 16551619 [PubMed - as supplied by publisher]

Free Radic Biol Med. 2006 Apr 1;40(7):1250-63. Epub 2005 Dec 19.

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Effect of heme and heme oxygenase-1 on vascular endothelial growth factor synthesis and angiogenic potency of human keratinocytes.

Jazwa A, Loboda A, Golda S, Cisowski J, Szelag M, Zagorska A, Sroczynska P, Drukala J, Jozkowicz A, Dulak J.

Department of Medical Biotechnology, Faculty of Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.

BACKGROUND: Skin injury leads to the release of heme, a potent prooxidant which is degraded by heme oxygenase-1 (HO-1) to carbon monoxide, iron, and biliverdin, subsequently reduced to bilirubin. Recently the involvement of HO-1 in angiogenesis has been shown; however, the role of heme and HO-1 in wound healing angiogenesis has not been yet investigated. RESULTS: Treatment of HaCaT keratinocytes with hemin (heme chloride) induced HO-1 expression and activity. The effect of heme on vascular endothelial growth factor (VEGF) synthesis is variable: induction is significant after a short, 6 h treatment with heme, while longer stimulation may attenuate its production. The involvement of HO-1 in VEGF synthesis was confirmed by inhibition of VEGF expression by SnPPIX, a blocker of HO activity and by attenuation of HO-1 mRNA expression with specific siRNA. Importantly, induction of HO-1 by hemin was able to overcome the inhibitory effect of high glucose on VEGF synthesis. Moreover, HO-1 expression was also induced in keratinocytes cultured in hypoxia, with concomitant augmentation of VEGF production, which was further potentiated by hemin stimulation. Accordingly, conditioned media from keratinocytes overexpressing HO-1 enhanced endothelial cell proliferation and augmented formation of capillaries in angiogenic assay in vitro. CONCLUSIONS: HO-1 is involved in hemin-induced VEGF expression in HaCaT and may play a role in hypoxic regulation of this protein. HO-1 overexpression may be beneficial in restoring the proper synthesis of VEGF disturbed in diabetic conditions.

J Hepatol. 2006 Feb 3; [Epub ahead of print]

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HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells.

Ghaziani T, Shan Y, Lambrecht RW, Donohue SE, Pietschmann T, Bartenschlager R, Bonkovsky HL.

Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA; The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA.

BACKGROUND/AIMS: Hepatitis C infection induces hepatic oxidative stress. Heme oxygenase (HO), the rate-controlling enzyme of heme catabolism, plays a key role as a protectant against oxidative, and other stresses. Other recent work has implicated Bach1, a heme binding protein that represses gene expression, in the regulation of HO-1 gene expression. METHODS: We investigated the effects of HCV polyprotein expression on expression of HO-1 and Bach1 genes in human hepatoma cells (Huh-7 cells). RESULTS: HO-1 was up-regulated in the cell line expressing HCV proteins from core up to the aminoterminal domain of NS3. Addition of increasing concentrations of N-acetylcysteine (NAC) led to down-regulation of HO-1 in cells expressing HCV proteins. In contrast, Bach1 was significantly down-regulated in these cells. Sodium arsenite, a strong inducer of oxidative stress and HO-1, reduced Bach1 expression in wild type Huh-7 cells, and NAC partially abrogated this decrease. CONCLUSIONS: Huh-7 cells expressing HCV proteins show significant up-regulation of the HO-1 gene, and reciprocal down-regulation of the Bach1 gene. Exogenous oxidative stressors and anti-oxidants can modulate expression of these genes. These and other results suggest a key role of down-regulation of Bach1 and up-regulation of HO-1 in diminishing cytotoxic effects of HCV proteins in human hepatocytes.

PMID: 16530877 [PubMed - as supplied by publisher]

J Hepatol. 2006 Feb 6; [Epub ahead of print]

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Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes.

Tron K, Samoylenko A, Musikowski G, Kobe F, Immenschuh S, Schaper F, Ramadori G, Kietzmann T.

Abteilung Gastroenterologie und Endokrinologie, Uniklinikum, Georg-August-Universitat Gottingen, D-37075 Gottingen, Germany.

BACKGROUND/AIMS: Heme oxygenase-1 (HO-1) can be induced by various stimuli, one of which is interleukin-6 (IL-6). Therefore, it the aim of this study was to elucidate the molecular mechanisms responsible for IL-6-dependent HO-1 induction in the liver. METHODS: The IL-6-dependent HO-1 regulation in rat primary hepatocytes and HepG2 hepatoma cells was studied by Northern and Western blot analyses, HO-1 promoter reporter gene assays and EMSA. RESULTS: The HO-1 expression was transcriptionally induced by IL-6 in a time- and dose-dependent manner. Activation of signal transducers and activators of transcription (STAT) factors by the IL-6 receptor was crucial for HO-1 induction. By contrast, negative regulation of HO-1 expression appeared to be mediated through the SH2-domain-containing tyrosine phosphatase-2 (SHP2)/ suppressors of cytokine signaling-3 (SOCS3) binding site within the gp130 IL-6 receptor subunit. Among the three putative STAT binding elements (SBE) in the HO-1 promoter, only the distal one was functional and when deleted, the remaining Luc induction was completely obliterated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. CONCLUSIONS: The HO-1 SBE3 mediates HO-1 gene induction by IL-6 mainly via activation of the Jak/STAT pathway.

PMID: 16510205 [PubMed - as supplied by publisher]

Cell Death Differ. 2006 Feb 17; [Epub ahead of print]

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Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin.

So HS, Kim HJ, Lee JH, Lee JH, Park SY, Park C, Kim YH, Kim JK, Lee KM, Kim KS, Chung SY, Jang WC, Moon SK, Chung HT, Park RK.

1Vestibulocochlear Research Center & Department of Microbiology, Wonkwang University School of Medicine, Jeonbuk 570-749, Korea.

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GSTmu-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.Cell Death and Differentiation advance online publication, 17 February 2006; doi:10.1038/sj.cdd.4401863.