Heme oxygenase-2 knockout neurons are less vulnerable to hemoglobin toxicity

Rogers, Bret; Yakopson, Vladimir; Teng, Zhi Ping; Guo, Yaping; Regan, Raymond F.

doi:10.1016/s0891-5849(03)00431-3

Cited by 82 publications

(109 citation statements)

References 56 publications

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“…The former process appears to predominate in heme-mediated injuries to cultured neurons. Targeted deletion of the HO-2 gene, the isoform that is constitutively expressed in neurons (Ewing and Maines, 1997), attenuated ROS formation, protein oxidation, and cell death due to Hb or hemin Rogers et al, 2003). These observations are consistent with reports that HO inhibitors attenuated edema and neuronal death after injection of whole blood or Hb into the rat striatum (Huang et al, 2002), rabbit thalamus (Koeppen et al, 2004), or pig frontal lobe .…”

Section: Introductionsupporting

confidence: 89%

Effect of Targeted Deletion of the Heme Oxygenase-2 Gene on Hemoglobin Toxicity in the Striatum

Chen

Benvenisti-Zarom

et al. 2005

J Cereb Blood Flow Metab

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The heme oxygenase (HO) enzymes catalyze the rate-limiting step in the breakdown of heme to iron, carbon monoxide, and biliverdin. A prior cell culture study demonstrated that deletion of HO-2, the isoform constitutively expressed in neurons, attenuated hemoglobin (Hb) neurotoxicity. The present study tested the hypothesis that HO-2 gene deletion is cytoprotective in a model of Hb toxicity in vivo. Stereotactic injection of 6 lL stroma-free Hb (SFHb) into the striatum significantly increased protein oxidation in wild-type mice at 24 to 72 h, as detected by an assay for carbonyl groups. At 72 h, carbonylation was increased 2.5-fold compared with that in the contralateral striatum. In HO-2 knockout mice, protein oxidation was not increased at 24 h, and was increased by only 1.7-fold at 72 h. Similarly, striatal lipid peroxidation, as detected by the malondialdehyde assay, was significantly greater in the SFHb-injected striata of wild-type mice than in knockout mice. Striatal cell viability, determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, was 45.0%76.3% of that in contralateral striata in wild-type mice at 72 h; it was increased to 85%7 8% in knockouts. Heme oxygenase-2 gene deletion did not alter weight loss or mortality after SFHb injection. Baseline striatal HO-1 expression was similar in knockout and wild-type mice; induction after SFHb injection occurred more rapidly in the latter. These results suggest that HO-2 gene deletion protects striatal cells from the oxidative toxicity of Hb in vivo. Pharmacologic or genetic strategies that target HO-2 may be beneficial after central nervous system hemorrhage, and warrant further investigation.

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Section: Introductionsupporting

confidence: 89%

Effect of Targeted Deletion of the Heme Oxygenase-2 Gene on Hemoglobin Toxicity in the Striatum

Chen

Benvenisti-Zarom

et al. 2005

J Cereb Blood Flow Metab

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“…Heme detoxification by brain endothelial cells possibly occurs during the initial phase of ICH and could be involved in the protective response against brain edema, based on the vasodilator activity of carbon monoxide in brain microvessels (Zakhary et al, 1996). However, some evidence from the literature point out that neurotoxic effects of hemoglobin seems to be dependent of HO-2, as deletion of this isoform not only reduced oxidative stress but also conferred resistance of neurons to hemoglobin (Rogers et al, 2003). In addition, HO-2 deletion also protected neurons from heme-induced toxic effects, in a mechanism mediated by oxidative stress (Regan et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The pathophysiology of ICH comprises a complex chain of events starting with blood-brain barrier disruption and infiltration of blood components into the brain parenchyma, resulting in a progressive edema, which starts in the first 24 h and remains elevated during several days (Koeppen et al, 2004). In many cases, inflammatory cell recruitment and activation contribute to the cerebral parenchyma damage, resulting in neuronal death, not only inside, but also around the perifocal reactive zone (Gong et al, 2000;Rogers et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

On the Fate of Extracellular Hemoglobin and Heme in Brain

Lara

Kahn

Fonseca

et al. 2009

J Cereb Blood Flow Metab

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Intracerebral hemorrhage (ICH) is a major cause of disability in adults worldwide. The pathophysiology of this syndrome is complex, involving both inflammatory and redox components triggered by the extravasation of blood into the cerebral parenchyma. Hemoglobin, heme, and iron released therein seem be important in the brain damage observed in ICH. However, there is a lack of information concerning hemoglobin traffic and metabolism in brain cells. Here, we investigated the fate of hemoglobin and heme in cultured neurons and astrocytes, as well as in the cortex of adult rats. Hemoglobin was made traceable by conjugation to Alexa 488, whereas a fluorescent heme analogue (tin-protoporphyrin IX) was prepared to allow heme tracking. Using fluorescence microscopy we observed that neurons were more efficient in uptake hemoglobin and heme than astrocytes. Exposure of cortical neurons to hemoglobin or heme resulted in an oxidative stress condition. Viability assays showed that neurons were more susceptible to both hemoglobin and heme toxicity than astrocytes. Together, these results show that neurons, rather than astrocytes, preferentially take up hemoglobin-derived products, indicating that these cells are actively involved in the ICH-associated brain damage.

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“…The HO-2-null mice are direct descendants of the HO-2 mutants produced by Poss and colleagues (Poss et al, 1995). These well-characterized HO-2-null mice have a C57BL/ 6×129/Sv genetic background (Rogers et al, 2003), which was used on age-and gendermatched controls (Jackson Laboratory, Bar Harbor, ME).…”

Section: Animalsmentioning

confidence: 99%

Exacerbated corneal inflammation and neovascularization in the HO-2 null mice is ameliorated by biliverdin

Bellner

Vitto

Patil

et al. 2008

Experimental Eye Research

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Heme oxygenase (HO-1 and HO-2) represents an intrinsic cytoprotective and anti-inflammatory system based on its ability to modulate leukocyte migration and to inhibit expression of inflammatory cytokines and proteins. HO-2 deletion leads to unresolved corneal inflammation and chronic inflammatory complications including ulceration, perforation and neovascularization. We examined the consequences of HO-2 deletion on hemangiogenesis and lymphangiogenesis in the model of suture-induced inflammatory neovascularization. A 8.0 silk suture was placed at the corneal apex of wild type and HO-2 null mice. Neovascularization was assessed by vital microscopy and quantified by image analysis. Hemangiogenesis and lymphangiogenesis were determined by immunofluorescence staining using anti-CD31 and anti-LYVE-1 antibodies, respectively. Inflammation was quantified by histology and myeloperoxidase activity. The levels of HO-1 expression and inflammatory cytokines were determined by real time PCR and ELISA, respectively. Corneal sutures produced a consistent inflammatory response and a time-dependent neovascularization. The response in HO-2 null mice was associated with a greater increase compared to the wild type in the number of leukocytes (827600±129000 vs. 294500±57510; p<0.05), neovessels measured by vital microscopy (21.91±1.05 vs. 12.77±1.55 mm; p<0.001) 4 days after suture placement. Hemangiogenesis but not lymphangiogenesis was more pronounced in HO-2 null mice compared to wild type mice. Induction of HO-1 in sutured corneas was greatly attenuated in HO-2 null corneas and treatment with biliverdin diminished the exaggerated inflammatory and neovascular response in HO-2 null mice. The demonstration that the inflammatory responses, including expression of proinflammatory proteins, inflammatory cell influx and hemangiogenesis are exaggerated in HO-2 knockout mice strongly supports the notion that the HO system is critical for controlling the inflammatory and neovascular response in the cornea. Hence, pharmacological amplification of this system may constitute a novel therapeutic strategy for the treatment of corneal disorders associated with excessive inflammation and neovascularization.

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Heme oxygenase-2 knockout neurons are less vulnerable to hemoglobin toxicity

Cited by 82 publications

References 56 publications

Effect of Targeted Deletion of the Heme Oxygenase-2 Gene on Hemoglobin Toxicity in the Striatum

Effect of Targeted Deletion of the Heme Oxygenase-2 Gene on Hemoglobin Toxicity in the Striatum

On the Fate of Extracellular Hemoglobin and Heme in Brain

Exacerbated corneal inflammation and neovascularization in the HO-2 null mice is ameliorated by biliverdin

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