Heme Oxygenase-1: A Novel Therapeutic Target in Oxidative Tissue Injuries

Takahashi, Toru; Morita, Kaoru; Akagi, Reiko; Sassa, Shigeru

doi:10.2174/0929867043365080

Cited by 182 publications

(120 citation statements)

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“…HO-1 is regarded as a regulatory protein during inflammatory situations (25,26). Therefore, the initial induction of HO-1 after TNF-· stimulation demonstrated in the present study is suggested to be a counter-regulation to avoid overstimulation of the proinflammatoric state of the cells.…”

Section: Discussionmentioning

confidence: 53%

Sevoflurane and isoflurane decrease TNF-α-induced gene expression in human monocytic THP-1 cells: Potential role of intracellular IκBα regulation

Boost

Leipold²,

Scheiermann³

et al. 2009

Int J Mol Med

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Abstract. The nuclear factor (NF)-κB/inhibitory (I)κB· pathway is one of the most important intracellular signal transduction pathways during inflammation which is induced by a variety of major early response cytokines. Recent studies suggest that volatile anesthetics interfere with inflammatory cytokine production through inhibition of intracellular signal transduction pathways. We, therefore, aimed to investigate the effects of the volatile anesthetics sevoflurane and isoflurane on NF-κB/IκB·-dependent intracellular signal transduction in human monocytic THP-1 cells induced by tumor necrosis factor-· (TNF-·) and production of interleukin-8 (IL-8) and downstream heme oxygenase-1 (HO-1). THP-1 cells, a human monocytic cell line, were used in an in vitro model which enables the exposure to volatile anesthetics. Using this model, THP-1 cells were subjected to sevoflurane or isoflurane exposure (1 MAC each) and were stimulated with TNF-· (50 or 100 ng/ml). Compared to untreated cells, expression of intracellular HO-1-protein and release of IL-8 into cell culture supernatants and corresponding mRNA expression were attenuated in THP-1 cells exposed to sevoflurane and isoflurane, respectively. Moreover, translocation of NF-κB and degradation of IκB· were markedly reduced by both anesthetics. Notably, under unstimulated conditions, exposure to sevoflurane induced a sustained upregulation of the IκB· content in THP-1 cells. We demonstrated inhibition of TNF-·-induced gene expression and release of IL-8 and HO-1 in human monocytic THP-1 cells exposed to both volatile anesthetics. This was associated with an upregulated intracellular IκB· content followed by decreased NF-κB translocation. This was more sustained during exposure to sevoflurane and may provide an additional intracellular mechanism for the anti-inflammatory effects associated with sevoflurane administration.

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Section: Discussionmentioning

confidence: 53%

Sevoflurane and isoflurane decrease TNF-α-induced gene expression in human monocytic THP-1 cells: Potential role of intracellular IκBα regulation

Boost

Leipold²,

Scheiermann³

et al. 2009

Int J Mol Med

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“…HO-1 is highly inducible by heme and a vast array of non-heme substances, including LPS. By contrast, HO-2 is expressed in a constitutive fashion, and appears to function as a heme-binding molecule in normal cells (19). The similarities and diversities of the NO/NOS and CO/ HO systems were well established in numerous studies (11,14), but the interactions between these systems have not yet been elucidated.…”

Section: Real-time Reverse Transcriptase-polymerase Chain Reaction (Rmentioning

confidence: 99%

The reciprocal relationship between heme oxygenase and nitric oxide synthase in the organs of lipopolysaccharide-treated rodents

et al. 2009

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The production of nitric oxide (NO) by inducible NO synthase (NOS) and carbon monoxide (CO) by inducible heme oxygenase (HO) contributes greatly to endotoxemia. Reciprocal relationships have been proposed between the NO/NOS and CO/HO systems. However, the interaction between these systems during endotoxemia is unclear, and it is unknown whether the interactive behavior differs among organs. Using endotoxic rats, we studied the effects of the inducible NOS (iNOS) inhibitor L-canavanine (CAN), and the HO inhibitor zinc protoporphyrin (ZPP) on gene expression and protein levels of iNOS, endothelial NOS (eNOS), inducible HO (HO-1), and constitutive HO (HO-2) in the brain, lung, heart, liver and kidney tissue. Intravenous injection of LPS significantly increased iNOS and HO-1 gene expression in all organs. The effects of LPS on eNOS gene expression differed among organs, with increased expression in the liver and kidney, and no change in the lung, brain and heart. ZPP administration down-regulated the LPS-induced increase in HO-1 expression and produced a further increase in iNOS expression in all organs. These data suggest that the CO/HO system modifies the NO/NOS system in endotoxic organs, and that there were only minor organ-specific behaviors in terms of the relationship between these systems in the organs examined.Endotoxemia, which can lead to shock, is a detrimental consequence of severe Gram-negative bacterial infection. Endotoxic shock is initiated by the release of bacterial cell wall-derived lipopolysaccharide (LPS) and the subsequent production of cytokines and vasoactive mediators (13). Gaseous mediators, namely nitric oxide (NO) and carbon monoxide (CO), and the major endogenous sources of these mediators, nitric oxide synthase (NOS) and heme oxygenase (HO), serve a pivotal role in endotoxemia. NO is an extensively studied molecule, and is known for its vasorelaxation and oxidative stressor properties during endotoxemia and septic shock. NO is produced by three distinct NOS enzymes. Two of these NOS isozymes are predominantly constitutively expressed in endothelial cells (eNOS) and in neuronal cells (nNOS), whereas the expression of the third isozyme (iNOS) is inducible in a variety of cells (e.g., macrophages, hepatocytes, vascular smooth muscle cells and cardiac myocytes) by numerous stimuli, including LPS (5, 13). iNOS is responsible for producing most of the NO that causes hypotension and oxidative stress during endotoxic shock, while eNOS is reported to have only a minor role in the pathophysiology of endotoxemia (9, 18). CO has been perceived for many years to be a life-threatening gas; recently, however, CO has become recognized to have anti-inflammatory and vasorelaxative properties and is essential for life. HO is the rate-limiting enzyme in the catabolism of heme, a process that promotes the formation of equimolar amounts of the bile pigment biliverdin, free iron, and CO (1). Together with the anti-inflam-

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“…Of these genes, heme oxygenase 1 (HMOX1) and activating transcription factor 3 (ATF3) showed remarkable overexpression (more than 8-fold) by high-concentration treatment at all 3 time points. HMOX1 was previously reported to be induced in kidney following toxic and ischemic insults (Nath, 2006, Takahashi et al, 2004.…”

Section: Discussionmentioning

confidence: 98%

Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

Ahn¹,

Baik²,

Ko³

et al. 2010

Genomics & Informatics

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Mercuric chloride, a model nephrotoxicant was used to elucidate time-and dose-dependent global gene expression changes associated with proximal tubular toxicity. Rat kidney cell lines NRK-52E cells were exposed for 2, 6 and 12 hours and with 3 different doses of mercuric chloride. Cell viability assay showed that mercuric chloride had toxic effects on NRK-52E cells causing 20% cell death (IC20) at 40μM concentration. We set this IC20 as high dose concentration and 1/5 and 1/25 concentration of LC20 were used as mid and low concentration, respectively. Analyses of microarray data revealed that 738 genes were differentially expressed (more than two-fold change and p＜0.05) by low concentration of mercuric chloride at least one time point in NRK-52E cells. 317 and 2,499 genes were differentially expressed at mid and high concentration of mercuric chloride, respectively. These deregulated genes showed a primary involvement with protein trafficking (CAV2, CANX, CORO1B), detoxification (GSTs) and immunity and defense (HMOX1, NQO1). Several of these genes were previously reported to be up-regulated in proximal tubule cells treated with nephrotoxicants and might be aid in promoting the predictive biomarkers for nephrotoxicity.

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Heme Oxygenase-1: A Novel Therapeutic Target in Oxidative Tissue Injuries

Cited by 182 publications

References 0 publications

Sevoflurane and isoflurane decrease TNF-α-induced gene expression in human monocytic THP-1 cells: Potential role of intracellular IκBα regulation

Sevoflurane and isoflurane decrease TNF-α-induced gene expression in human monocytic THP-1 cells: Potential role of intracellular IκBα regulation

The reciprocal relationship between heme oxygenase and nitric oxide synthase in the organs of lipopolysaccharide-treated rodents

Effects of Mercuric Chloride on Gene Expression in NRK-52E Cells

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