MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice

Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Blood 2013-10, Vol.122 (15), p.2757-2764
Hauptverfasser: Belcher, John D., Young, Mark, Chen, Chunsheng, Nguyen, Julia, Burhop, Kenneth, Tran, Phuc, Vercellotti, Gregory M.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 2764
container_issue 15
container_start_page 2757
container_title Blood
container_volume 122
creator Belcher, John D.
Young, Mark
Chen, Chunsheng
Nguyen, Julia
Burhop, Kenneth
Tran, Phuc
Vercellotti, Gregory M.
description Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-ĸB activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-ĸB activation, microvascular stasis, and mortality in transgenic sickle mouse models. •Carbon monoxide treatment of murine sickle mice can ameliorate inflammation and vaso-occlusion.•MP4CO induces heme oxygenase-1 and Nrf2 to mediate these salutatory effects.
doi_str_mv 10.1182/blood-2013-02-486282
format Article
fullrecord <record><control><sourceid>elsevier_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4067504</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006497120497861</els_id><sourcerecordid>S0006497120497861</sourcerecordid><originalsourceid>FETCH-LOGICAL-c463t-300468777d9edb691a49c8773225e92bf5846df3c76de3fb4979182adacf870e3</originalsourceid><addsrcrecordid>eNp9UctuFDEQtCIQWQJ_EEX-gBjaj3ldIkWrQJCClgOcLY_ds2syY6_s2U3yF3wyThYCXDi1uuyqru4i5JTDO85b8b4fY3RMAJcMBFNtLVpxRBa8Ei0DEPCCLACgZqpr-DF5nfN3AK6kqF6RYyE7aFXdLsiPz1_UcnVODd3i-mE0Mzq6wSmux9j7QLOZd-kJvPPzhlqT-hjoFEO89w7Pqc-FOUW3K8yYaBzo9YrxgodhNNNkZh9DEQ-O7k2OLFo77nLBygc6JxPyGoO3NHt7OyKdvMU35OVgxoxvf9UT8u3D1dflNbtZffy0vLxhVtVyZhKg-G-axnXo-rrjRnW29FKICjvRD1XZzw3SNrVDOfTlCl25mnHGDm0DKE_IxUF3u-sndBZD8TPqbfKTSQ86Gq__fQl-o9dxrxXUTQWqCKiDgE0x54TDM5eDfkxIPyWkHxPSIPQhoUI7-3vuM-l3JH-MYdl-7zHpbD0Gi84ntLN20f9_wk9eU6U-</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Belcher, John D. ; Young, Mark ; Chen, Chunsheng ; Nguyen, Julia ; Burhop, Kenneth ; Tran, Phuc ; Vercellotti, Gregory M.</creator><creatorcontrib>Belcher, John D. ; Young, Mark ; Chen, Chunsheng ; Nguyen, Julia ; Burhop, Kenneth ; Tran, Phuc ; Vercellotti, Gregory M.</creatorcontrib><description>Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-ĸB activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-ĸB activation, microvascular stasis, and mortality in transgenic sickle mouse models. •Carbon monoxide treatment of murine sickle mice can ameliorate inflammation and vaso-occlusion.•MP4CO induces heme oxygenase-1 and Nrf2 to mediate these salutatory effects.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2013-02-486282</identifier><identifier>PMID: 23908468</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Anemia, Sickle Cell - drug therapy ; Anemia, Sickle Cell - metabolism ; Anemia, Sickle Cell - mortality ; Animals ; Carbon Monoxide - metabolism ; Carbon Monoxide - pharmacology ; Disease Models, Animal ; Female ; Guaiacol - analogs &amp; derivatives ; Heme Oxygenase-1 - metabolism ; Hemin - metabolism ; Hemin - pharmacology ; Hemoglobins - metabolism ; Hemoglobins - pharmacology ; Humans ; Inflammation - drug therapy ; Inflammation - metabolism ; Inflammation - mortality ; Male ; Maleimides - metabolism ; Maleimides - pharmacology ; Membrane Proteins - metabolism ; Mice ; Mice, Transgenic ; Microcirculation - drug effects ; Microcirculation - physiology ; NF-E2-Related Factor 2 - metabolism ; NF-kappa B - metabolism ; Polyethylene Glycols - metabolism ; Polyethylene Glycols - pharmacology ; Vascular Biology ; Vasculitis - drug therapy ; Vasculitis - metabolism ; Vasculitis - mortality</subject><ispartof>Blood, 2013-10, Vol.122 (15), p.2757-2764</ispartof><rights>2013 American Society of Hematology</rights><rights>2013 by The American Society of Hematology 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-300468777d9edb691a49c8773225e92bf5846df3c76de3fb4979182adacf870e3</citedby><cites>FETCH-LOGICAL-c463t-300468777d9edb691a49c8773225e92bf5846df3c76de3fb4979182adacf870e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23908468$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Belcher, John D.</creatorcontrib><creatorcontrib>Young, Mark</creatorcontrib><creatorcontrib>Chen, Chunsheng</creatorcontrib><creatorcontrib>Nguyen, Julia</creatorcontrib><creatorcontrib>Burhop, Kenneth</creatorcontrib><creatorcontrib>Tran, Phuc</creatorcontrib><creatorcontrib>Vercellotti, Gregory M.</creatorcontrib><title>MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice</title><title>Blood</title><addtitle>Blood</addtitle><description>Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-ĸB activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-ĸB activation, microvascular stasis, and mortality in transgenic sickle mouse models. •Carbon monoxide treatment of murine sickle mice can ameliorate inflammation and vaso-occlusion.•MP4CO induces heme oxygenase-1 and Nrf2 to mediate these salutatory effects.</description><subject>Anemia, Sickle Cell - drug therapy</subject><subject>Anemia, Sickle Cell - metabolism</subject><subject>Anemia, Sickle Cell - mortality</subject><subject>Animals</subject><subject>Carbon Monoxide - metabolism</subject><subject>Carbon Monoxide - pharmacology</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Guaiacol - analogs &amp; derivatives</subject><subject>Heme Oxygenase-1 - metabolism</subject><subject>Hemin - metabolism</subject><subject>Hemin - pharmacology</subject><subject>Hemoglobins - metabolism</subject><subject>Hemoglobins - pharmacology</subject><subject>Humans</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - metabolism</subject><subject>Inflammation - mortality</subject><subject>Male</subject><subject>Maleimides - metabolism</subject><subject>Maleimides - pharmacology</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microcirculation - drug effects</subject><subject>Microcirculation - physiology</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>NF-kappa B - metabolism</subject><subject>Polyethylene Glycols - metabolism</subject><subject>Polyethylene Glycols - pharmacology</subject><subject>Vascular Biology</subject><subject>Vasculitis - drug therapy</subject><subject>Vasculitis - metabolism</subject><subject>Vasculitis - mortality</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UctuFDEQtCIQWQJ_EEX-gBjaj3ldIkWrQJCClgOcLY_ds2syY6_s2U3yF3wyThYCXDi1uuyqru4i5JTDO85b8b4fY3RMAJcMBFNtLVpxRBa8Ei0DEPCCLACgZqpr-DF5nfN3AK6kqF6RYyE7aFXdLsiPz1_UcnVODd3i-mE0Mzq6wSmux9j7QLOZd-kJvPPzhlqT-hjoFEO89w7Pqc-FOUW3K8yYaBzo9YrxgodhNNNkZh9DEQ-O7k2OLFo77nLBygc6JxPyGoO3NHt7OyKdvMU35OVgxoxvf9UT8u3D1dflNbtZffy0vLxhVtVyZhKg-G-axnXo-rrjRnW29FKICjvRD1XZzw3SNrVDOfTlCl25mnHGDm0DKE_IxUF3u-sndBZD8TPqbfKTSQ86Gq__fQl-o9dxrxXUTQWqCKiDgE0x54TDM5eDfkxIPyWkHxPSIPQhoUI7-3vuM-l3JH-MYdl-7zHpbD0Gi84ntLN20f9_wk9eU6U-</recordid><startdate>20131010</startdate><enddate>20131010</enddate><creator>Belcher, John D.</creator><creator>Young, Mark</creator><creator>Chen, Chunsheng</creator><creator>Nguyen, Julia</creator><creator>Burhop, Kenneth</creator><creator>Tran, Phuc</creator><creator>Vercellotti, Gregory M.</creator><general>Elsevier Inc</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20131010</creationdate><title>MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice</title><author>Belcher, John D. ; Young, Mark ; Chen, Chunsheng ; Nguyen, Julia ; Burhop, Kenneth ; Tran, Phuc ; Vercellotti, Gregory M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-300468777d9edb691a49c8773225e92bf5846df3c76de3fb4979182adacf870e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Anemia, Sickle Cell - drug therapy</topic><topic>Anemia, Sickle Cell - metabolism</topic><topic>Anemia, Sickle Cell - mortality</topic><topic>Animals</topic><topic>Carbon Monoxide - metabolism</topic><topic>Carbon Monoxide - pharmacology</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Guaiacol - analogs &amp; derivatives</topic><topic>Heme Oxygenase-1 - metabolism</topic><topic>Hemin - metabolism</topic><topic>Hemin - pharmacology</topic><topic>Hemoglobins - metabolism</topic><topic>Hemoglobins - pharmacology</topic><topic>Humans</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - metabolism</topic><topic>Inflammation - mortality</topic><topic>Male</topic><topic>Maleimides - metabolism</topic><topic>Maleimides - pharmacology</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microcirculation - drug effects</topic><topic>Microcirculation - physiology</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>NF-kappa B - metabolism</topic><topic>Polyethylene Glycols - metabolism</topic><topic>Polyethylene Glycols - pharmacology</topic><topic>Vascular Biology</topic><topic>Vasculitis - drug therapy</topic><topic>Vasculitis - metabolism</topic><topic>Vasculitis - mortality</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Belcher, John D.</creatorcontrib><creatorcontrib>Young, Mark</creatorcontrib><creatorcontrib>Chen, Chunsheng</creatorcontrib><creatorcontrib>Nguyen, Julia</creatorcontrib><creatorcontrib>Burhop, Kenneth</creatorcontrib><creatorcontrib>Tran, Phuc</creatorcontrib><creatorcontrib>Vercellotti, Gregory M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Belcher, John D.</au><au>Young, Mark</au><au>Chen, Chunsheng</au><au>Nguyen, Julia</au><au>Burhop, Kenneth</au><au>Tran, Phuc</au><au>Vercellotti, Gregory M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2013-10-10</date><risdate>2013</risdate><volume>122</volume><issue>15</issue><spage>2757</spage><epage>2764</epage><pages>2757-2764</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Transgenic sickle mice expressing βS hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-ĸB activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-ĸB activation, microvascular stasis, and mortality in transgenic sickle mouse models. •Carbon monoxide treatment of murine sickle mice can ameliorate inflammation and vaso-occlusion.•MP4CO induces heme oxygenase-1 and Nrf2 to mediate these salutatory effects.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>23908468</pmid><doi>10.1182/blood-2013-02-486282</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0006-4971
ispartof Blood, 2013-10, Vol.122 (15), p.2757-2764
issn 0006-4971
1528-0020
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4067504
source MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection
subjects Anemia, Sickle Cell - drug therapy
Anemia, Sickle Cell - metabolism
Anemia, Sickle Cell - mortality
Animals
Carbon Monoxide - metabolism
Carbon Monoxide - pharmacology
Disease Models, Animal
Female
Guaiacol - analogs & derivatives
Heme Oxygenase-1 - metabolism
Hemin - metabolism
Hemin - pharmacology
Hemoglobins - metabolism
Hemoglobins - pharmacology
Humans
Inflammation - drug therapy
Inflammation - metabolism
Inflammation - mortality
Male
Maleimides - metabolism
Maleimides - pharmacology
Membrane Proteins - metabolism
Mice
Mice, Transgenic
Microcirculation - drug effects
Microcirculation - physiology
NF-E2-Related Factor 2 - metabolism
NF-kappa B - metabolism
Polyethylene Glycols - metabolism
Polyethylene Glycols - pharmacology
Vascular Biology
Vasculitis - drug therapy
Vasculitis - metabolism
Vasculitis - mortality
title MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T17%3A17%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-elsevier_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MP4CO,%20a%20pegylated%20hemoglobin%20saturated%20with%20carbon%20monoxide,%20is%20a%20modulator%20of%20HO-1,%20inflammation,%20and%20vaso-occlusion%20in%20transgenic%20sickle%20mice&rft.jtitle=Blood&rft.au=Belcher,%20John%20D.&rft.date=2013-10-10&rft.volume=122&rft.issue=15&rft.spage=2757&rft.epage=2764&rft.pages=2757-2764&rft.issn=0006-4971&rft.eissn=1528-0020&rft_id=info:doi/10.1182/blood-2013-02-486282&rft_dat=%3Celsevier_pubme%3ES0006497120497861%3C/elsevier_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/23908468&rft_els_id=S0006497120497861&rfr_iscdi=true