Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity

Li, Zhi; Chen-Roetling, Jing; Regan, Raymond F.

doi:10.1080/10715760902942808

Cited by 16 publications

(11 citation statements)

References 40 publications

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“…Nevertheless, studies of various cell lines and in vivo studies have shown that a number of conditions or agents known to increase cell H 2 O 2 and O 2 Á -levels induce the reversible inactivation of IRP1 (12,18,63,193,200), and this makes it possible to conclude that IRP1 downregulation (aimed at decreasing TfR1 while increasing ferritin levels, and hence diminishing the LIP) is a common response designed to prevent the enhanced formation of ROS. In line with this, increased ferritin synthesis has been documented in a number of cell types exposed to oxidative stimuli (14,205), whereas the overexpression of either the ferritin H (36, 52, 150) or ferritin L subunit (110,150) reduces oxidative damage.…”

Section: B Oxidative Stressmentioning

confidence: 89%

Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

Recalcati

Minotti²,

Cairo

2010

Antioxidants & Redox Signaling

106

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Eukaryotic cells require iron for survival but, as an excess of poorly liganded iron can lead to the catalytic production of toxic radicals that can damage cell structures, regulatory mechanisms have been developed to maintain appropriate cell and body iron levels. The interactions of iron responsive elements (IREs) with iron regulatory proteins (IRPs) coordinately regulate the expression of the genes involved in iron uptake, use, storage, and export at the post-transcriptional level, and represent the main regulatory network controlling cell iron homeostasis. IRP1 and IRP2 are similar (but not identical) proteins with partially overlapping and complementary functions, and control cell iron metabolism by binding to IREs (i.e., conserved RNA stem-loops located in the untranslated regions of a dozen mRNAs directly or indirectly related to iron metabolism). The discovery of the presence of IREs in a number of other mRNAs has extended our knowledge of the influence of the IRE/IRP regulatory network to new metabolic pathways, and it has been recently learned that an increasing number of agents and physiopathological conditions impinge on the IRE/IRP system. This review focuses on recent findings concerning the IRP-mediated regulation of iron homeostasis, its alterations in disease, and new research directions to be explored in the near future.

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Section: B Oxidative Stressmentioning

confidence: 89%

Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

Recalcati

Minotti²,

Cairo

2010

Antioxidants & Redox Signaling

106

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“…Evidence suggests that FHC, which contains a ferroxidase center, oxidizes Fe II for FLC which, in turn, mineralizes and stores Fe III [152, 153]. In the brain, ferritin is found in the choroid plexus [154], astrocytes [155], oligodendrocytes, pyramidal neurons, microglia, and BMVEC [1]. Ferritin is trafficked across BMVEC via transcytosis from P1-P7; this method of trafficking is significantly diminished after complete ensheathment of the BMVEC by astrocytic endfeet at P14 [10].…”

Section: Proteins Involved In the Efflux Of Iron From Bmvecmentioning

confidence: 99%

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

McCarthy

Kosman

2014

Cell. Mol. Life Sci.

113

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There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease.

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“…Since each ferritin molecule can sequester over 4000 ferric ions in it mineral core [13], we hypothesized that the increase in the labile iron pool that we have previously observed in these cultures after hemin treatment [16] would be reduced by metHb or thrombin preconditioning. Cytosolic labile iron, as detected by calcein fluorescence quenching [21], was significantly decreased in cultures pre-treated with 3 μM metHb followed by 30 μM hemin, compared with control cultures pretreated with MEM10 medium alone before hemin exposure (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cortical glial cultures (> 90 % GFAP +) were prepared from 2–3 day old C57BL/6 X 129/Sv mice that were bred in our animal facility, following a protocol that was approved by the local Institutional Animal Care and Use Committee and previously described in detail [16]. Approximately two-thirds of the culture medium was replaced at 5–6 days in vitro and then twice weekly, using growth medium containing minimal essential medium (MEM), 23 mM glucose, 2 mM glutamine, and 10 % equine serum (Hyclone, Logan, UT, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Changes in cytosolic redox active iron (the labile iron pool) were detected by quantifying calcein fluorescence quenching in hemin-treated cultures, as previously described [16, 21]. Cultures were pretreated with 3 μM metHb or 5 units/ml thrombin for 24 h, alone or with chelators, following the protocol described in the cytotoxicity experiments section.…”

Section: Methodsmentioning

confidence: 99%

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Effect of Iron Chelators on Methemoglobin and Thrombin Preconditioning

Chen-Roetling

Sinanan

Regan

2012

Transl. Stroke Res.

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Cell loss immediately adjacent to an intracerebral hemorrhage may be mediated in part by the toxicities of extracellular hemoglobin (Hb) and thrombin. However, at low concentrations, these proteins induce tolerance to hemin and iron that may limit further peri-hematomal injury as erythrocyte lysis progresses. The mechanisms mediating these preconditioning effects have not been completely defined, but increased expression of both heme oxygenase (HO)-1 and iron binding proteins likely contributes. In the present study, we hypothesized that iron chelator therapy would attenuate this protective response. Pretreatment of cortical glial cultures (> 90 % GFAP+) with 3 μM methemoglobin (metHb) or 5 units/ml thrombin for 24 h was nontoxic per se, and increased HO-1 and ferritin expression. When challenged with a toxic concentration of hemin, the increase in cellular redox-active iron was attenuated in preconditioned cultures and cell survival was increased. However, if cultures were pretreated with metHb or thrombin plus deferoxamine or 2,2′-bipyridyl, ferritin induction was prevented and cellular redox-active iron increased with hemin treatment. Preconditioning-mediated cytoprotection was consistently reduced by deferoxamine, while 2,2′-bipyridyl had a variable effect. Neither chelator altered HO-1 expression. A cytoprotective response was preserved when chelator therapy was limited to 11 hours of the 24 h preconditioning interval. These results suggest a potentially deleterious effect of continuous iron chelator therapy after ICH. Intermittent therapy may remove peri-hematomal iron without negating the benefits of exposure to low concentrations of Hb or thrombin.

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Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity

Cited by 16 publications

References 40 publications

Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

Iron Regulatory Proteins: From Molecular Mechanisms to Drug Development

Iron transport across the blood–brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy

Effect of Iron Chelators on Methemoglobin and Thrombin Preconditioning

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