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

Qu, Yan; Chen, Jing; Benvenisti-Zarom, Luna; Ma, Xin; Regan, Raymond F.

doi:10.1038/sj.jcbfm.9600143

Cited by 37 publications

(52 citation statements)

References 64 publications

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“…The same authors found that subsequently heme‐oxygenase 1, an enzyme, degrading hemoglobin into carbon monoxide, biliverdin, and iron was markedly increased. Intracellular iron overload was shown to result in lipid peroxidation and free radical formation leading to delayed edema and acute brain injury 35, 36, 37, 38, 39. In accordance with these findings, brain tissue damage was reported to be reduced in experimental SAH by the knockout of lipocalin 2, an iron transport protein 40.…”

Section: Discussionmentioning

confidence: 52%

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Scherfler

Schiefecker

Delazer

et al. 2016

Ann Clin Transl Neurol

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Objective MRI parameters of iron concentration (R2*, transverse relaxation rate), microstructural integrity (mean diffusivity and fractional anisotropy), as well as gray and white matter volumes were analyzed in patients with subarachnoid hemorrhage (SAH) and uncomplicated clinical course to detect the evolution of brain tissue changes 3 weeks and 12 months after ictus.Methods MRI scans of 14 SAH patients (aneurysm of the anterior communicating artery, n = 5; no aneurysm n = 9) were compared with 14 age‐matched healthy control subjects. Statistical parametric mapping (SPM) was applied to objectively identify focal changes of MRI parameters throughout the entire brain and to correlate image parameters with neuropsychological measures.Results SPM localized significant bilateral increases in R2* signal within the white matter compartment of the temporal and parietal lobe and the cingulate gyrus (P < 0.001) which did not change significantly at 12 months. Significant gray matter volume reduction of the left insula and superior temporal gyrus (P < 0.001), as well as decreases in fractional anisotropy of the cingulate gyrus (P < 0.01) were also evident at 12 months. Significant correlations were found between fractional anisotropy signal alterations adjacent to the left middle and superior frontal gyrus and cognitive parameters of executive dysfunction (P < 0.001).InterpretationThe study indicates that iron is trapped predominantly throughout large portions of the white matter compartment in SAH patients at 12 months postbleeding. Increased disintegration of fiber tracts colocalizing with iron overload and correlating with lower executive function performance suggests that the white matter compartment is primarily susceptible toward long‐term damage in patients with good clinical grade SAH.

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Section: Discussionmentioning

confidence: 52%

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Scherfler

Schiefecker

Delazer

et al. 2016

Ann Clin Transl Neurol

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“…In HO2-KO mice, oxidative stress estimated by lipid peroxidation in the hemorrhage-injured brain was greatly increased [43,137,138]. HO-2 gene deletion also increased brain injury volume and potentiated extended neuronal damage caused by brain hemorrhage [43,[137][138][139]. These studies emphasize that HO-2 is a crucial neuroprotective enzyme in detoxifying high levels of heme in the brain [139].…”

Section: E Ho-2 Protection Against Hemorrhage and Traumatic Brain Inmentioning

confidence: 77%

“…Heme is a potent HO-1 inducer, and HO-1 is induced in the brain following traumatic brain injury and hemorrhage [43]. However, recent studies pinpoint to importance of HO-2 in protecting the brain from consequences of hemorrhage and traumatic brain injury [43,[135][136][137][138][139]. In HO2-KO mice, oxidative stress estimated by lipid peroxidation in the hemorrhage-injured brain was greatly increased [43,137,138].…”

Section: E Ho-2 Protection Against Hemorrhage and Traumatic Brain Inmentioning

confidence: 99%

“…However, recent studies pinpoint to importance of HO-2 in protecting the brain from consequences of hemorrhage and traumatic brain injury [43,[135][136][137][138][139]. In HO2-KO mice, oxidative stress estimated by lipid peroxidation in the hemorrhage-injured brain was greatly increased [43,137,138]. HO-2 gene deletion also increased brain injury volume and potentiated extended neuronal damage caused by brain hemorrhage [43,[137][138][139].…”

Section: E Ho-2 Protection Against Hemorrhage and Traumatic Brain Inmentioning

confidence: 99%

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Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via posttranslational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK Ca channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK Ca channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidantgenerating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress. KeywordsHeme oxygenase; cerebral protection; cerebrovascular disease; oxidative stress; seizures; carbon monoxide; bilirubin Vasodilator role of CO in cerebral circulation A. Vasoactive effects of exogenous CO in cerebral vesselsExperimental studies in newborn pigs conducted using in vivo and in vitro approaches demonstrate that exogenous CO is a potent vasodilator in cerebral circulation [1][2][3][4][5][6][7]. CO can be delivered to the brain as CO gas dissolved in a physiological buffer or as recently introduced CO-releasing molecules (CO-RMs) that release CO on illumination (dimanganese decacarbonyl, DMDC) or when dissolved in physiologically buffered solutions (sodium boranocarbonate, CO-RM-A1) [8,9]. In vivo, CO, DMDC and CORM-A1 applied directly to the brain surface under the cranial window at concentrations ≥10 −7 M causes dilation of pial arterioles, major resistance brain vessels that define the cerebral blood

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“…In animal models, injection of lysed erythrocytes, Hb, and iron into the brain causes significant cell death and produces a hostile environment that impairs survival of transplanted cells, thereby limiting cell transplants as potential therapy for ICH. 10,20,21 However, some studies also suggest that low levels of ROS contribute to stem cell proliferation, self-renewal, and neurogenesis. 22,23 This suggests that the amount of ROS is important for regulating cell fate.…”

Section: Discussionmentioning

confidence: 99%

Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice

Wakai

Narasimhan

Sakata

et al. 2016

J Cereb Blood Flow Metab

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Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage.

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

Cited by 37 publications

References 64 publications

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Longitudinal profile of iron accumulation in good‐grade subarachnoid hemorrhage

Cerebroprotective Functions of HO-2

Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice

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