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Characterization of Plasma Labile Heme in Hemolytic Conditions

2017-08Journal article Open access
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dc.contributor.authorGouveia, Zélia
dc.contributor.authorCarlos, Ana Rita
dc.contributor.authorYuan, Xiaojing
dc.contributor.authorAires-da-Silva, Frederico
dc.contributor.authorStocker, Roland
dc.contributor.authorJ. Maghzal, Ghassan
dc.contributor.authorLeal, Sónia S.
dc.contributor.authorGomes, Cláudio M.
dc.contributor.authorTodorovic, Smilja
dc.contributor.authorIranzo, Olga
dc.contributor.authorRamos, Susana
dc.contributor.authorSantos, Ana Catarina
dc.contributor.authorHamza, Iqbal
dc.contributor.authorGonçalves, João
dc.contributor.authorSoares, Miguel P.
dc.date.accessioned2017-08-28T11:51:43Z
dc.date.available2019-08-01T00:30:09Z
dc.date.issued2017-08
dc.descriptionThe deposited article is the accepted manuscript (post-print version) posted online 7 August 2017 and provided by The Febs Journal. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. The deposited article version contains attached the supplementary materials within the pdf. This publication hasn't any creative commons license associated, although it is in open access.pt_PT
dc.description.abstractExtracellular hemoglobin (Hb), a byproduct of hemolysis, can release its prosthetic heme groups upon oxidation. This produces metabolically active heme that is exchangeable between acceptor proteins, macromolecules and low molecular weight ligands, termed here labile heme. As it accumulates in plasma labile heme acts in a pro-oxidant manner and regulates cellular metabolism while exerting pro-inflammatory and cytotoxic effects that foster the pathogenesis of hemolytic diseases. Here we developed and characterized a panel of heme-specific single domain antibodies (sdAbs) that together with a cellular-based heme reporter assay, allow for quantification and characterization of labile heme in plasma during hemolytic conditions. Using these approaches we demonstrate that labile heme generated during hemolytic conditions is bound to plasma molecules with an affinity higher than 10(-7) M and that 2-8% (~2-5 μM) of the total amount of heme detected in plasma can be internalized by bystander cells, i.e. bioavailable heme. Acute, but not chronic, hemolysis is associated with transient reduction of plasma heme binding capacity (HBC1/2 ), that is, the ability of plasma molecules to bind labile heme with an affinity higher than 10(-7) M. The heme-specific sdAbs neutralize the pro-oxidant activity of soluble heme in vitro, suggesting that these maybe used to counter the pathologic effects of labile heme during hemolytic conditions. Finally, we show that heme-specific sdAbs can be used to visualize cellular heme. In conclusion, we describe a panel of heme-specific sdAbs that when used with other approaches provide novel insights to the pathophysiology of heme. This article is protected by copyright. All rights reserved.pt_PT
dc.description.sponsorshipFundação para a Ciência e Tecnologia grants: (RECI-IMI-IMU-0038-2012, PTDC/SAU-TOX/116627/2010, HMSP-ICT/0018/2011, SFRH/BD/44828/2008, SFRH/BPD/47477/2008, PTDC/SAU-FAR/119173/2010, IF/01010/2013/CP1183/CT0001); ERC grants: (ERC-2011-AdG 294709-DAMAGECONTROL); NHMRC Senior Principal Research Fellowship: (1003484).pt_PT
dc.description.versioninfo:eu-repo/semantics/acceptedVersionpt_PT
dc.identifier.citationGouveia, Z., Carlos, A. R., Yuan, X., Aires-da-Silva, F., Stocker, R., J. Maghzal, G., Leal, S. S., Gomes, C. M., Todorovic, S., Iranzo, O., Ramos, S., Santos, A. C., Hamza, I., Gonçalves, J. and Soares, M. P. (), Characterization of Plasma Labile Heme in Hemolytic Conditions. FEBS J. Accepted Author Manuscript. doi:10.1111/febs.14192pt_PT
dc.identifier.doi10.1111/febs.14192pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.7/782
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationNHMRC Senior Principal Research Fellowship 1003484pt_PT
dc.relationTREAT LIVER DISEASES BY TARGETING HEPATOCYTE NECROPTOSIS
dc.relationPATHOLOGIC CONSEQUENCES OF HEME RELEASE FROM HEMOPROTEINS.
dc.relationMISFOLDING AND AGGREGATION OF CU/ZN SUPEROXIDE DISMUTASE SOD1: ROLE OF METAL BINDING AND IMPLICATIONS IN ALS NEURODEGENERATION
dc.relationArmAb: New strategy of ADC for arming antibodies in cancer therapy
dc.relationTissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases
dc.relation.publisherversionhttp://onlinelibrary.wiley.com/doi/10.1111/febs.14192/abstractpt_PT
dc.subjecthemolysispt_PT
dc.subjecthemoglobinpt_PT
dc.subjecthemept_PT
dc.subjectmalariapt_PT
dc.subjectsickle cell diseasept_PT
dc.subjectantibody engineeringpt_PT
dc.subjectsingle‐domain antibodypt_PT
dc.titleCharacterization of Plasma Labile Heme in Hemolytic Conditionspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTREAT LIVER DISEASES BY TARGETING HEPATOCYTE NECROPTOSIS
oaire.awardTitlePATHOLOGIC CONSEQUENCES OF HEME RELEASE FROM HEMOPROTEINS.
oaire.awardTitleMISFOLDING AND AGGREGATION OF CU/ZN SUPEROXIDE DISMUTASE SOD1: ROLE OF METAL BINDING AND IMPLICATIONS IN ALS NEURODEGENERATION
oaire.awardTitleArmAb: New strategy of ADC for arming antibodies in cancer therapy
oaire.awardTitleTissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/RECI%2FIMI-IMU%2F0038%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-TOX%2F116627%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/HMSP-ICT%2F0018%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F44828%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F47477%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-FAR%2F119173%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F01010%2F2013%2FCP1183%2FCT0001/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/FP7/294709/EU
oaire.citation.endPage55pt_PT
oaire.citation.startPage1pt_PT
oaire.citation.titleFEBS Journalpt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamInvestigador FCT
oaire.fundingStreamFP7
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
rcaap.embargofctThe deposited article has 24 months of embargo period in terms of access, because of the journal's policies and the publisher's copyright policy, which require a period of embargo of 12 months after the date of the publication, and since the paper has not been published yet, the library service put in this upload an embargo period superior than 12 months, as a securing measure.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
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