Heme oxygenase-1 induction protects murine cortical astrocytes from hemoglobin toxicity

Regan, Raymond F.; Guo, Yaping; Kumar, Nidhi

doi:10.1016/s0304-3940(00)00817-x

Cited by 63 publications

(61 citation statements)

References 23 publications

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“…Consistent with prior observations [21], treatment of WT astrocyte cultures with 3-30 μM Hb for 75-120h resulted in no cell injury, as detected by LDH assay (Fig. 1A).…”

Section: Vulnerability Of Astrocytes and Neurons To Hemoglobinsupporting

confidence: 92%

“…Astrocytes from mice that were genetically identical except that they lacked the HO-1 gene sustained significant oxidative injury after the same treatment. These results are very similar to those observed when wildtype astrocyte cultures were treated with Hb in the presence of HO inhibitors [21], and indicate that the exacerbation of injury by these inhibitors was due at least in part to HO inhibition rather than some nonspecific effect.…”

Section: Discussionsupporting

confidence: 81%

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Effect of heme oxygenase-1 on the vulnerability of astrocytes and neurons to hemoglobin

Chen-Roetling

Regan

2006

Biochemical and Biophysical Research Communications

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The heme oxygenase (HO) enzymes catalyze the rate-limiting step of heme breakdown. Prior studies have demonstrated that the vulnerability of neurons and astrocytes to hemoglobin is modified in cells lacking HO-2, the constitutive isoform. The present study assessed the effect of the inducible isoform, HO-1. Wild-type astrocytes treated for 3-5 days with 3-30 μM hemoglobin sustained no loss of viability, as quantified by LDH and MTT assays. The same treatment resulted in death of 25-50% of HO-1 knockout astrocytes, and a fourfold increase in protein oxidation. Cell injury was attenuated by transfer of the HO-1 gene, but not by bilirubin, the antioxidant heme breakdown product. Conversely, neuronal protein oxidation and cell death after hemoglobin exposure were similar in wild-type and HO-1 knockout cultures. These results suggest that HO-1 induction protects astrocytes from the oxidative toxicity of Hb, but has no effect on neuronal injury.

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“…Consistent with prior observations [21], treatment of WT astrocyte cultures with 3-30 μM Hb for 75-120h resulted in no cell injury, as detected by LDH assay (Fig. 1A).…”

Section: Vulnerability Of Astrocytes and Neurons To Hemoglobinsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 81%

Effect of heme oxygenase-1 on the vulnerability of astrocytes and neurons to hemoglobin

Chen-Roetling

Regan

2006

Biochemical and Biophysical Research Communications

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“…Both wildtype and HO-2 knockout astrocytes are highly resistant to Hb in culture. This resistance is mediated at least in part by HO activity, because it is markedly diminished by HO inhibitors (Regan et al, 2000). Astrocytes are quite vulnerable to the rapid injury produced by hemin, the oxidized form of heme that accumulates to high micromolar concentrations in hematomas (Letarte et al, 1993).…”

Section: Ho-1 Band Dencitymentioning

confidence: 99%

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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“…Conversely, HO-1 is involved in astrocyte and neuron heme tolerance (Regan et al, 2000;ChenRoetling and Regan, 2006), whereas the function of HO-2 in neuronal protection against heme remains controversial (Doré et al, 1999;Rogers et al, 2003). Zinc protoporphyrin IX, a potent HO inhibitor, has recently shown to be beneficial in a rabbit model of ICH, indicating that iron released from heme degradation may be involved in the pathogenesis of ICH (Gong et al, 2006).…”

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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Heme oxygenase-1 induction protects murine cortical astrocytes from hemoglobin toxicity

Cited by 63 publications

References 23 publications

Effect of heme oxygenase-1 on the vulnerability of astrocytes and neurons to hemoglobin

Effect of heme oxygenase-1 on the vulnerability of astrocytes and neurons to hemoglobin

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

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