Heme Oxygenase‐1: Transducer of Pathological Brain Iron Sequestration under Oxidative Stress

Schipper, Hyman M.

doi:10.1196/annals.1306.007

Cited by 110 publications

(101 citation statements)

References 42 publications

(59 reference statements)

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“…In the normal brain and in cerebral vessels, HO-1 is undetectable, with the exception of few neuronal populations, mainly olfactory and hippocampal neurons [37][38][39][40][41][42]. In sharp contrast to other tissues, brain and cerebrovascular HO-1 is not readily induced by oxidative stress, with the exception of very limited array of strong pro-oxidant signals.…”

Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 96%

“…In sharp contrast to other tissues, brain and cerebrovascular HO-1 is not readily induced by oxidative stress, with the exception of very limited array of strong pro-oxidant signals. Among few described pathophysiological interventions that upregulate HO-1 in the brain in vivo, are hemorrhage [41][42][43] and hyperthermia [38]. However, epileptic seizures that cause a burst of oxidative stress in the brain failed to induce HO-1 in the brain parenchyma or in cerebral vasculature within 4-24 h [39].…”

Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

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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Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 96%

Section: Heme Oxygenase Isoforms In Cerebral Circulationmentioning

confidence: 99%

Cerebroprotective Functions of HO-2

Parfenova¹,

Leffler²

2008

CPD

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“…The high degree of Cygb-ir/PV-ir co-expression therefore shows for the first time that Cygb-expressing neurons are primarily inhibitory interneurons. The high degree of co-expression with HO-1 is notable as HO-1 is an oxidative stress-inducible protein and enzymatic degradation of heme leads to the production of iron, biliverdin (an antioxidant) and CO (34). Cygb may therefore either be a heme substrate for HO-1 or alternatively, Cygb may, in these HO-1-expressing neurons, regulate the level of the gas-neurontransmitter CO produced by HO-1 in a similar way to that proposed for NO (18,19,21).…”

Section: Discussionmentioning

confidence: 99%

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

2014

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Abstract. Cytoglobin (Cygb), a novel oxygen-binding protein, is expressed in the majority of tissues and has been proposed to function in nitric oxide (NO) metabolism in the vasculature and to have cytoprotective properties. However, the overall functions of Cygb remain elusive. Cygb is also expressed in a subpopulation of brain neurons. Recently, it has been shown that stress upregulates Cygb expression in the brain and the majority of neuronal nitric oxide synthase (nNOS)-positive neurons, an enzyme that produces NO, co-express Cygb. However, there are more neurons expressing Cygb than nNOS, thus a large number of Cygb neurons remain uncharacterized by the neurochemical content. The aim of the present study was to provide an additional and more detailed neurochemical phenotype of Cygb-expressing neurons in the rat hippocampus. The rat hippocampus was chosen due to the abundance of Cygb, as well as this limbic structure being an important target in a number of neurodegenerative diseases. Using triple immunohistochemistry, it was demonstrated that nearly all the parvalbumin-and heme oxygenase 1-positive neurons co-express Cygb and to a large extent, these neuron populations are distinct from the population of Cygb neurons co-expressing nNOS. Furthermore, it was shown that the majority of neurons expressing somastostatin and vasoactive intestinal peptide also co-express Cygb and nNOS. Detailed information regarding the neurochemical phenotype of Cygb neurons in the hippocampus can be a valuable tool in determining the function of Cygb in the brain.

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“…Under oxidative stress, astrocytes may become rich in iron through an overexpression of heme oxygenase-1, an enzyme that promotes mitochondria iron sequestration. [72][73][74] Thus, the activated iron-rich astrocytes may survive an inflammation and become detectable by MR imaging. 72,75 Furthermore, the manganese-dependent enzymes glutamine synthetase and manganese superoxide dismutase (MnSOD) may be abundant in activated astrocytes.…”

Section: Astrocytesmentioning

confidence: 99%

<i>In Vivo</i> Brain MR Imaging at Subnanoliter Resolution: Contrast and Histology

2016

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This article provides an overview of in vivo magnetic resonance (MR) imaging contrasts obtained for mammalian brain in relation to histological knowledge. Emphasis is paid to the (1) significance of high spatial resolution for the optimization of T 1 , T 2 , and magnetization transfer contrast, (2) use of exogenous extra-and intracellular contrast agents for validating endogenous contrast sources, and (3) histological structures and biochemical compounds underlying these contrasts and (4) their relevance to neuroradiology. Comparisons between MR imaging at subnanoliter resolution and histological data indicate that (a) myelin sheaths, (b) nerve cells, and (c) the neuropil are most responsible for observed MR imaging contrasts, while (a) diamagnetic macromolecules, (b) intracellular paramagnetic ions, and (c) extracellular free water, respectively, emerge as the dominant factors. Enhanced relaxation rates due to paramagnetic ions, such as iron and manganese, have been observed for oligodendrocytes, astrocytes, microglia, and blood cells in the brain as well as for nerve cells. Taken together, a plethora of observations suggests that the delineation of specific structures in high-resolution MR imaging of mammalian brain and the absence of corresponding contrasts in MR imaging of the human brain do not necessarily indicate differences between species but may be explained by partial volume effects. Second, paramagnetic ions are required in active cells in vivo which may reduce the magnetization transfer ratio in the brain through accelerated T 1 recovery. Third, reductions of the magnetization transfer ratio may be more sensitive to a particular pathological condition, such as astrocytosis, microglial activation, inflammation, and demyelination, than changes in relaxation. This is because the simultaneous occurrence of increased paramagnetic ions (i.e., shorter relaxation times) and increased free water (i.e., longer relaxation times) may cancel T 1 or T 2 effects, whereas both processes reduce the magnetization transfer ratio.

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Heme Oxygenase‐1: Transducer of Pathological Brain Iron Sequestration under Oxidative Stress

Cited by 110 publications

References 42 publications

Cerebroprotective Functions of HO-2

Cerebroprotective Functions of HO-2

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

<i>In Vivo</i> Brain MR Imaging at Subnanoliter Resolution: Contrast and Histology

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