Cell-Free Oxyhemoglobin in Cerebrospinal Fluid After Aneurysmal Subarachnoid Hemorrhage: Biomarker and Potential Therapeutic Target

Hugelshofer, Michael; Sikorski, Christopher; Seule, Martin; Deuel, Jeremy; Muroi, Carl; Seboek, Martina; Akeret, Kevin; Buzzi, Raphael M; Regli, Luca; Schaer, Dominik J.; Keller, Emanuela

doi:10.1016/j.wneu.2018.08.141

Cited by 33 publications

(33 citation statements)

References 11 publications

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“…Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm with DIND had higher cumulative cell-free Hb concentrations in CSF over a time period of 14 days after aSAH than patients without DIND (6). Vasospasm remains an important feature of DIND.…”

Section: Introductionmentioning

confidence: 91%

“…Within days after aSAH, red blood cells in the cerebrospinal fluid (CSF) are disintegrated by immunological and nonimmunological processes. This erythrolysis is a temporally variable process, which results in individual time profiles of cell-free hemoglobin (Hb) in the CSF (6). We previously reported that elevated concentrations of Hb in CSF correlate with the occurrence of DIND, which suggests that cell-free Hb accelerates pathological processes in patients with aSAH (6).…”

Section: Introductionmentioning

confidence: 99%

“…This erythrolysis is a temporally variable process, which results in individual time profiles of cell-free hemoglobin (Hb) in the CSF (6). We previously reported that elevated concentrations of Hb in CSF correlate with the occurrence of DIND, which suggests that cell-free Hb accelerates pathological processes in patients with aSAH (6). Cell-free Hb has been discussed for many years as a driver of damage and as a cause of vasospasm after aSAH (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

Hugelshofer

Buzzi

Schaer

et al. 2019

Journal of Clinical Investigation

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Statistics. We used JMP software from SAS (versions 13 or 14) for all analyses. Data are presented with all data points plotted. Overlayed diamonds represent mean, 95% CI, and overlap marks (horizontal lines above and below the mean line), which define statistical significant difference between groups if not overlapping (P < 0.05). Groups were compared with 1-way ANOVA, applying a Tukey-Kramer posttest correcting for multiple comparisons. A P value of less than 0.05 was considered statistically significant.Study approval. All animal studies were approved by the cantonal veterinary authorities "Kantonale Tierversuchskommission Zürich." The clinical study (CSF sampling) was approved by the local ethical review board of the Kanton of Zurich, and written consent was obtained from all patients or their legal representatives.

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Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

Hugelshofer

Buzzi

Schaer

et al. 2019

Journal of Clinical Investigation

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“…For the in vitro neuron injury model, oxyHb was used to mimic the injury that occurs to neurons in the brain after hemorrhagic stroke [5,6]. In brief, the cells were seeded in culture plates and cultured with complete medium (5% CO 2 , 37°C) for 24 h. Then, the medium was removed and the cells were exposed to 10 μM oxyHb (Sigma-Aldrich, MO, USA) in complete medium for 24 h. The dose and time point of oxyHb were selected according to our previous study [4].…”

Section: Oxyhemoglobin-induced Neuron Injury Modelmentioning

confidence: 99%

MiR-137 Boosts the Neuroprotective Effect of Endothelial Progenitor Cell Derived-Exosomes in Oxyhemoglobin Treated SH-SY5Y Cells Partially via COX2/PGE2 Pathway

Wang

Chen

et al. 2020

Preprint

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Background: We have previously verified the beneficial effects of exosomes from endothelial progenitor cells (EPC-EXs) in ischemic stroke. However, the effects of EPC-EXs in hemorrhagic stroke have not been investigated. Additionally, miR-137 is reported to regulate ferroptosis and to be involved in the neuroprotection against ischemic stroke. Hence, the present work explored the effects of miR-137-overexpressing EPC-EXs on apoptosis, mitochondrial dysfunction, and ferroptosis in oxyhemoglobin (oxyHb)-injured neurons.Methods: The lentiviral miR-137 was transfected into EPCs and then the EPC-EXs were collected. RT-PCR was used to detect the miR-137 level in EPCs, EXs and neurons. The uptake mechanisms of EPC-EXs in neurons were explored by the co-incubation of Dynasore, Pitstop 2, Ly294002 and Genistein. After the transfection of different types of EPC-EXs, flow cytometry and expression of cytochrome c and cleaved caspase-3 were used to detect the apoptosis of oxyHb-injured neurons. Neuronal mitochondrial function was assessed by reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP) depolarization, and cellular ATP content. Cell ferroptosis was measured by lipid peroxidation, iron overload, degradation of glutathione and glutathione peroxidase 4. Additionally, recombinational PGE2 was used to detect if activation of COX2/PGE2 pathway could reverse the protection of miR-137 overexpression.Results: The present work showed 1) EPC-EXs could be taken in by SH-SY5Y cells via caveolin-/clathrin-mediated pathways and macropinocytosis; 2) miR-137 was decreased in neurons after oxyHb treatment, and EXs miR-137 could restore the miR-137 levels; 3) EXs miR-137 worked better than EXs in reducing the number of apoptotic neurons and pro-apoptotic protein expression after oxyHb treatment; 4) EXs miR-137 are more effective in improving the cellular MMP, ROS and ATP level; 5) EXs miR-137 , but not EXs, protected oxyHb-treated neurons against lipid peroxidation, iron overload, degradation of glutathione and glutathione peroxidase 4; 6) EXs miR-137 suppressed the expression of the COX2/PGE2 pathway, and activation of the pathway could partially reverse the neuroprotective effects of EXs miR-137 .Conclusion: MiR-137 overexpression boosts the neuroprotective effects of EPC-EXs against apoptosis and mitochondrial dysfunction in oxyHb-treated neurons. Furthermore, EXs miR-137 rather than EXs can restore the decrease in miR-137 levels and inhibit ferroptosis, and the protection mechanism might involve the miR-137-COX2/PGE2 signaling pathway.

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“…Extravasation of blood into the intraventricular space triggers a cascade of events including the release of various vasoactive and proinflammatory molecules from the blood (reviewed in [46]). Previous studies showed that cell-free Hb and Hb metabolites are present in CSF following different types of intracranial hemorrhage including IVH [31,[47][48][49]. Among the different redox states of Hb, metHb was detected in CSF samples obtained following IVH in preterm infants as well as in an experimental rabbit model of IVH and its role in the neuroinflammatory response has been shown [47].…”

mentioning

confidence: 99%

Formation and Detection of Highly Oxidized Hemoglobin Forms in Biological Fluids during Hemolytic Conditions

Nyakundi

Erdei

Tóth

et al. 2020

Oxidative Medicine and Cellular Longevity

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Hemolytic diseases are characterized by an accelerated breakdown of red blood cells (RBCs) and the release of hemoglobin (Hb). Following, RBC lysis Hb oxidation occurs with the formation of different redox states of Hb (metHb and ferrylHb) and the release of heme. ferrylHb is unstable and decomposes to metHb with the concomitant formation of globin radicals and eventually covalently crosslinked Hb multimers. The goal of the present study was to determine the concentrations of the different redox states of Hb in biological samples during hemolytic conditions. We used plasma and urine samples of mice with intravascular hemolysis and human cerebrospinal fluid (CSF) samples following intraventricular hemorrhage. Because ferrylHb is highly unstable, we also addressed the fate of this species. metHb and free heme time-dependently accumulate in plasma and CSF samples following intravascular hemolysis and intraventricular hemorrhage, respectively. ferrylHb is hardly detectable in the biological samples during hemolytic conditions. Under in vitro conditions, ferrylHb decomposes quickly to metHb, which process is associated with the formation of covalently crosslinked Hb multimers. We detected these covalently crosslinked Hb multimers in plasma, urine, and CSF samples during hemolytic conditions. Because globin modification is specific for these Hb forms, we propose to call this heterogeneous form of Hb produced during ferrylHb decomposition as globin-modified oxidized Hb (gmoxHb). Understanding the formation and the contribution of gmoxHb species to the pathogenesis of hemolytic conditions could have therapeutic implications in the treatment of hemolytic diseases.

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Cell-Free Oxyhemoglobin in Cerebrospinal Fluid After Aneurysmal Subarachnoid Hemorrhage: Biomarker and Potential Therapeutic Target

Cited by 33 publications

References 11 publications

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

MiR-137 Boosts the Neuroprotective Effect of Endothelial Progenitor Cell Derived-Exosomes in Oxyhemoglobin Treated SH-SY5Y Cells Partially via COX2/PGE2 Pathway

Formation and Detection of Highly Oxidized Hemoglobin Forms in Biological Fluids during Hemolytic Conditions

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