Knockout of ho-1 protects the striatum from ferrous iron-induced injury in a male-specific manner in mice

Wang, Li Fang; Yokoyama, Kazunari K.; Lin, Chih‐Lung; Chen, Tzu-Yin; Hsiao, Hsiu-Wen; Chiang, Pei-Chi; Hsu, Chin

doi:10.1038/srep26358

Cited by 24 publications

(19 citation statements)

References 54 publications

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“…1F). HO-1 is strongly linked to oxidative stress, and previous reports have demonstrated that HO-1 is a key factor in aggravating the ICH condition 37,38 .…”

Section: Discussionmentioning

confidence: 91%

Intracellular Fe2+ accumulation in endothelial cells and pericytes induces blood-brain barrier dysfunction in secondary brain injury after brain hemorrhage

Imai

Iwata

Hirayama

et al. 2019

Sci Rep

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After intracranial hemorrhage (ICH), iron is released from the hematoma and induces secondary brain injury. However, the detail effect of iron on blood-brain barrier (BBB) function is still unknown. We investigated whether hemoglobin (Hb), ferrous ammonium sulfate (FAS) or hemin which contains iron have the detrimental effect on both human brain microvascular endothelial cells and pericytes by cellular function analysis in vitro . We developed an iron (Fe 2+ )-detectable probe, Si-RhoNox-1, to investigate intracellular Fe 2+ accumulation (Fe 2+ intra ). After FAS treatment, there was the correlation between Fe 2+ intra and cell death. Moreover, Hb or hemin treatment induced cell death, increased reactive oxygen species and promoted Fe 2+ intra in both cells. These changes were inhibited by the Fe 2+ chelator, 2,2′-bipyridil (BP). Furthermore, hemin induced endothelial barrier dysfunction via disruption of junction integrity. Based on in vitro studies, we used a hemin-injection ICH mice model in vivo . Hemin injection (10 mM/10 µL, i.c.) induced deleterious effects including BBB hyper-permeability, neuronal deficits, neuronal damage, altered proteins expression, and Fe 2+ intra in BBB composed cells. Lastly, BP (40 mg/kg, i.p.) administration attenuated neuronal deficits at 3 days after surgery. Collectively, Hb or hemin damaged BBB composed cells via Fe 2+ intra . Therefore, the regulation of the Fe 2+ movement in BBB might be effective for treatment of ICH.

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“…1F). HO-1 is strongly linked to oxidative stress, and previous reports have demonstrated that HO-1 is a key factor in aggravating the ICH condition 37,38 .…”

Section: Discussionmentioning

confidence: 91%

Intracellular Fe2+ accumulation in endothelial cells and pericytes induces blood-brain barrier dysfunction in secondary brain injury after brain hemorrhage

Imai

Iwata

Hirayama

et al. 2019

Sci Rep

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“…After 72 hours, the above changes weakened, but still higher than the normal group. Study by Wang et al19 showed that overexpression of HO-1 has damaging effects on ICH brain injury induced by ferrous citrate.…”

Section: Discussionmentioning

confidence: 99%

The role of heme oxygenase-1 (HO-1) in the regulation of inflammatory reaction, neuronal cell proliferation and apoptosis in rats after intracerebral hemorrhage (ICH)

Xue-zheng¹,

2016

NDT

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ObjectiveTo investigate the role of heme oxygenase-1 (HO-1) in the regulation of inflammatory reaction, neuronal cell proliferation and apoptosis in rats after intracerebral hemorrhage (ICH).MethodsThirty-six adult Sprague Dawley (SD) male rats were randomly divided into sham operation, ICH and zinc protoporphyrin (ZPP) group. Rats (except for the sham operation group) were given 50 μL stereotactic injection of autologous blood from the femoral artery into the caudate nucleus, to establish an ICH model. In addition, rats in the ZPP group were given 10 mg/kg intraperitoneal injection of ZPP. At day 3 postoperative, neurobehavioral changes and brain water content were evaluated, brain tissue HO-1 expression was detected with immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR), brain tissue apoptosis was evaluated with TUNEL method, Caspase 3, Caspase 8 and Caspase 9 activity were detected with colorimetric method, level of TNF-α, IL-1β, IL-6 and IL-8 were measured with the enzyme-linked immunosorbent assay (ELISA), while Bcl-2, Bax, p-NF-κB p65 and p-IκBα protein expression were detected with Western blot.ResultsICH group compared to sham operation: HO-1 positive rate and mRNA expression were increased, neurological deficit score and cell apoptosis rate were increased, Caspase 3, Caspase 8 and Caspase 9 activity were increased, level of TNF-α, IL-1β, IL-6 and IL-8 were increased, Bcl-2 expression was downregulated, Bax, p-NF-κB p65 and p-IκBα expression were upregulated. The differences were statistically significant (P<0.01). ZPP group compared to ICH: HO-1 positive rate and mRNA expression were decreased, neurological deficit score and cell apoptosis rate were decreased, Caspase 3, Caspase 8, Caspase 9 activity were decreased, level of TNF-α, IL-1β, IL-6 and IL-8 were decreased, Bcl-2 expression was upregulated, Bax, p-NF-κB p65 and p-IκBα expression were downregulated, and the differences were statistically significant (P<0.01).ConclusionHO-1 inhibitor, ZPP does have a protective effect on ICH rats. This might be due to its inhibition to the inflammatory reaction and neuronal cell apoptosis.

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“…Increased expression of HFE and H-ferritin was observed in 6-month old H67D mice, alongside astrogliosis, increased protein oxidation, expression of

and HO-1, suggestive of heightened metabolic and oxidative stress. Accordingly, the striatum of HO-1 knockout mice was protected from iron-mediated injury in males but not females (Wang et al, 2016b ). Meanwhile, H67D mice at 12-months had augmented H- and L-ferritin accompanied by attenuated Tf expression, indicating increased storage of iron (Nandar et al, 2013 ).…”

Section: Effect Of Systemic Iron Overload On Brain Ironmentioning

confidence: 99%

The Aging of Iron Man

Ashraf

Clark

2018

Front. Aging Neurosci.

129

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Brain iron is tightly regulated by a multitude of proteins to ensure homeostasis. Iron dyshomeostasis has become a molecular signature associated with aging which is accompanied by progressive decline in cognitive processes. A common theme in neurodegenerative diseases where age is the major risk factor, iron dyshomeostasis coincides with neuroinflammation, abnormal protein aggregation, neurodegeneration, and neurobehavioral deficits. There is a great need to determine the mechanisms governing perturbations in iron metabolism, in particular to distinguish between physiological and pathological aging to generate fruitful therapeutic targets for neurodegenerative diseases. The aim of the present review is to focus on the age-related alterations in brain iron metabolism from a cellular and molecular biology perspective, alongside genetics, and neuroimaging aspects in man and rodent models, with respect to normal aging and neurodegeneration. In particular, the relationship between iron dyshomeostasis and neuroinflammation will be evaluated, as well as the effects of systemic iron overload on the brain. Based on the evidence discussed here, we suggest a synergistic use of iron-chelators and anti-inflammatories as putative anti-brain aging therapies to counteract pathological aging in neurodegenerative diseases.

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Knockout of ho-1 protects the striatum from ferrous iron-induced injury in a male-specific manner in mice

Cited by 24 publications

References 54 publications

Intracellular Fe2+ accumulation in endothelial cells and pericytes induces blood-brain barrier dysfunction in secondary brain injury after brain hemorrhage

Intracellular Fe2+ accumulation in endothelial cells and pericytes induces blood-brain barrier dysfunction in secondary brain injury after brain hemorrhage

The role of heme oxygenase-1 (HO-1) in the regulation of inflammatory reaction, neuronal cell proliferation and apoptosis in rats after intracerebral hemorrhage (ICH)

The Aging of Iron Man

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