Heme Oxygenase-1-derived Carbon Monoxide Requires the Activation of Transcription Factor NF-κB to Protect Endothelial Cells from Tumor Necrosis Factor-α-mediated Apoptosis

Brouard, Sophie; Berberat, Pascal O.; Tobiasch, Edda; Seldon, Mark P.; Bach, Fritz H.; Soares, Miguel P.

doi:10.1074/jbc.m108317200

Cited by 274 publications

(193 citation statements)

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“…In support of this hypothesis, Sarady et al have demonstrated that HO-1 overexpression in a murine macrophage cell line reduced LPSmediated GM-CSF expression by inhibiting IκB-α degradation [44]. In contrast, Brouard, et al have demonstrated that HO-1-derived CO requires the activation of NF-κB to protect endothelial cells from TNF-α-mediated apoptosis (45). These conflicting observations suggest that the role of NF-κB in HO-1-mediated cell survival is cell-and stimulus-specific.…”

Section: Discussionmentioning

confidence: 99%

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Zabalgoitia

Colston

Reddy

et al. 2008

Free Radical Biology and Medicine

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The objective of this study was to determine whether heme oxygenase-1 (HO-1) or heme metabolites exert cytoprotective effects on interleukin-18-mediated endothelial cell (EC) death. Treatment with IL-18 increased NF-κB activation, PTEN induction, suppressed Akt activation, and stimulated EC death. While ectopic expression of p65 enhanced PTEN transcription, adenoviral transduction of dnIκB-α, dnp65, or dnIKKβ was inhibitory. Furthermore, IL-18 suppressed HO-1 mRNA expression via enhanced mRNA degradation. Overexpression of HO-1, treatment with HO-1 inducer hemin or the CO donor Cobalt (III) protoporphyrin IX all reversed IL-18-mediated NF-κB activation, PTEN induction, Akt suppression, and EC death. Furthermore, hemin induced HO-1 expression, and HO-1 knockdown, HO-1 inhibition, or CO scavengers all reversed the pro-survival effects of hemin. In addition, the CO donors CORM-1 and CORM-3 and the heme metabolites biliverdin and bilirubin attenuated IL-18-induced EC death via a similar signaling pathway. IL-18 induced p38α MAPK activation, and suppressed p38β isoform expression. While p38α knockdown attenuated, p38β knockdown potentiated IL-18-mediated EC death. Hemin and HO-1 reversed IL-18-mediated p38α induction, and restored p38β levels. These results demonstrate that IL-18 suppresses HO-1 expression and induces EC death. HO-1 overexpression, HO-1 induction, or treatment with heme metabolites all reverse IL-18-mediated p38α MAPK and NF-κB activation, PTEN induction, Akt suppression, and EC death. Thus, HO-1 inducers and CO donors may have the therapeutic potential to effectively block IL-18 signaling and reduce IL-18-dependent vascular injury and inflammation.

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Section: Discussionmentioning

confidence: 99%

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Zabalgoitia

Colston

Reddy

et al. 2008

Free Radical Biology and Medicine

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“…Indeed, each of these products has been shown to exert cytoprotective effects. CO protects endothelial cells from apoptosis in vitro 22 by inhibiting inducible NO-synthase activity, 23 which is a key factor for GalN/LPS-induced liver injury, 24 and prevents anti-CD95-induced apoptosis in the liver. 5 Bilirubin, an intracellular reaction product of BV, represents a physiologically important defense against reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

et al. 2004

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Induction of the heme-degrading enzyme heme oxygenase-1 (HO-1) has been shown to be beneficial in terms of improvement of liver allograft survival and prevention of CD95-mediated apoptosis in the liver. In the present study, we investigated the effects of HO-1, and its products carbon monoxide (CO), biliverdin (BV), and iron/ferritin, in a mouse model of results in the production of carbon monoxide (CO), free iron, and biliverdin (BV). HO-1, in contrast to the second isoform HO-2, is inducible by various stimuli. 1,2 To investigate HO effects in vitro as well as in vivo, HO-1 can be induced by application of cobalt-protoporphyrin-IX (CoPP), for example, while tin-protoporphyrin-IX (SnPP) suppresses HO activity. 3,4 In the liver, administration of CoPP to mice results in HO-1 expression in hepatocytes as well as in Kupffer cells. 5 In vivo, HO-1 induction has been shown previously to protect mice from apoptotic liver damage 5 and to protect rats from liver graft rejection as well as from ischemia/reperfusion injury. 6 -8 To investigate mechanisms of cytokine-dependent liver injury, mice can be sensitized with the hepatocytespecific transcriptional inhibitor D-galactosamine (GalN) in combination with the macrophage activator lipopolysaccharide (LPS). 9 In this GalN/LPS model, mice develop severe liver injury, which is dependent on tumor necrosis factor (TNF) 10,11 and interferon ␥ (IFN-␥) 12 induction, while interleukin (IL) 10 prevents injury. 13 In the present study we show that HO-1, induced by CoPP, protects mice from GalN/LPS-induced liver injury, prolongs survival, and reduces cytokine expression. Protection from liver damage could also be achieved by pretreatment with the HO products CO and BV, but not by ferritin. Prolongation of survival and cytokine reduction was only detectable in mice pretreated with a combination of both hepatoprotective products CO and BV. Materials and MethodsAnimals. BALB/c-mice (6-8 weeks old; weight range, 18-22 g) were obtained from the animal facilities of the

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“…activity below this threshold level, the antiapoptotic action of HO-1 would be disabled, which would most probably have detrimental effects (44). We propose that HO-1 has reached a functional compromise in that it blocks NF-B-mediated transcription activity in a manner that inhibits the expression of a subset of NF-B dependent genes, e.g., E-selectin and VCAM-1, but allows the expression of other NF-B-dependent genes, e.g., ICAM-1, including those required to support its antiapoptotic action (29). Whether this selective effect is purely due to the extent of NF-B inhibition or whether there are additional mechanisms that could account for it is not clear.…”

Section: Ho-1 Promotes the Activation Of The P38 Mapk Signal Transducmentioning

confidence: 99%

“…Although speculative, this may have important implications for the overall biological function of HO-1, because we have recently shown that, to prevent EC apoptosis, HO-1 requires that NF-B activation must be maintained above a certain threshold level (29). This level of NF-B activity seems to be required to sustain the expression of a subset of NF-B-dependent antiapoptotic genes that interact functionally with HO-1-derived CO to prevent EC apoptosis (29). Thus, if HO-1 would suppress NF-B FIGURE 13.…”

Section: Ho-1 Promotes the Activation Of The P38 Mapk Signal Transducmentioning

confidence: 99%

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Heme Oxygenase-1 Modulates the Expression of Adhesion Molecules Associated with Endothelial Cell Activation

Soares

Seldon

Grégoire

et al. 2004

The Journal of Immunology

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412

271

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Heme oxygenase-1 (HO-1) cleaves the porphyrin ring of heme into carbon monoxide, Fe2+, and biliverdin, which is then converted into bilirubin. Heme-derived Fe2+ induces the expression of the iron-sequestering protein ferritin and activates the ATPase Fe2+-secreting pump, which decrease intracellular free Fe2+ content. Based on the antioxidant effect of bilirubin and that of decreased free cellular Fe2+, we questioned whether HO-1 would modulate the expression of proinflammatory genes associated with endothelial cell (EC) activation. We tested this hypothesis specifically for the genes E-selectin (CD62), ICAM-1 (CD54), and VCAM-1 (CD106). We found that HO-1 overexpression in EC inhibited TNF-α-mediated E-selectin and VCAM-1, but not ICAM-1 expression, as tested at the RNA and protein level. Heme-driven HO-1 expression had similar effects to those of overexpressed HO-1. In addition, HO-1 inhibited the activation of NF-κB, a transcription factor required for TNF-α-mediated up-regulation of these genes in EC. Bilirubin and/or Fe2+ chelation mimicked the effects of HO-1, whereas biliverdin or carbon monoxide did not. In conclusion, HO-1 inhibits the expression of proinflammatory genes associated with EC activation via a mechanism that is associated with the inhibition of NF-κB activation. This effect of HO-1 is mediated by bilirubin and/or by a decrease of free intracellular Fe2+ but probably not by biliverdin or carbon monoxide.

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Heme Oxygenase-1-derived Carbon Monoxide Requires the Activation of Transcription Factor NF-κB to Protect Endothelial Cells from Tumor Necrosis Factor-α-mediated Apoptosis

Abstract: We have shown that carbon monoxide (CO) generated by heme oxygenase-1 (HO-1) protects endothelial cells (

Cited by 274 publications

References 49 publications

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death

Cooperative effect of biliverdin and carbon monoxide on survival of mice in immune-mediated liver injury

Heme Oxygenase-1 Modulates the Expression of Adhesion Molecules Associated with Endothelial Cell Activation

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