Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury

Background & Aims: Liver ischemia/reperfusion (I/R) injury is a frequent cause of organ dysfunction. Loss of the oxygen sensor prolyl hydroxylase domain enzyme 1 (PHD1) causes tolerance of skeletal muscle to hypoxia. We assessed whether loss or short-term silencing of PHD1 could likewise ind...

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Autores: Schneider, Martin, Van Geyte, Katie, Fraisl, Peter, Kiss, Judit, Aragonés, Julián, Mazzone, Massimiliano, Mairbäurl, Heimo, De Bock, Katrien, Ho Jeoung, Nam, Mollenhauer, Martin, Georgiadou, Maria, Bishop, Tammie, Roncal Mancho, Carmen, Sutherland, Andrew, Jordan, Benedicte, Gallez, Bernard, Weitz, Jürgen, Harris, Robert A., Maxwell, Patrick, Baes, Myriam, Ratcliffe, Peter, Carmeliet, Peter
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2010
País:España
Institución:Universidad Pública de Navarra
Repositorio:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/56174
Acceso en línea:https://hdl.handle.net/2454/56174
Access Level:acceso abierto
Palabra clave:PHD1
Prolyl hydroxylase
Ischemia/Reperfusion
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spelling Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injurySchneider, MartinVan Geyte, KatieFraisl, PeterKiss, JuditAragonés, JuliánMazzone, MassimilianoMairbäurl, HeimoDe Bock, KatrienHo Jeoung, NamMollenhauer, MartinGeorgiadou, MariaBishop, TammieRoncal Mancho, CarmenSutherland, AndrewJordan, BenedicteGallez, BernardWeitz, JürgenHarris, Robert A.Maxwell, PatrickBaes, MyriamRatcliffe, PeterCarmeliet, PeterPHD1Prolyl hydroxylaseIschemia/ReperfusionBackground & Aims: Liver ischemia/reperfusion (I/R) injury is a frequent cause of organ dysfunction. Loss of the oxygen sensor prolyl hydroxylase domain enzyme 1 (PHD1) causes tolerance of skeletal muscle to hypoxia. We assessed whether loss or short-term silencing of PHD1 could likewise induce hypoxia tolerance in hepatocytes and protect them against hepatic I/R damage. Methods: Hepatic ischemia was induced in mice by clamping of the portal vessels of the left lateral liver lobe; 90 minutes later livers were reperfused for 8 hours for I/R experiments. Hepatocyte damage following ischemia or I/R was investigated in PHD1-deficient (PHD1-/-) and wild-type mice or following short hairpin RNA-mediated short-term inhibition of PHD1 in vivo. Results: PHD1-/- livers were largely protected against acute ischemia or I/R injury. Among mice subjected to hepatic I/R followed by surgical resection of all nonischemic liver lobes, more than half of wild-type mice succumbed, whereas all PHD1-/- mice survived. Also, short-term inhibition of PHD1 through RNA interference-mediated silencing provided protection against I/R. Knockdown of PHD1 also induced hypoxia tolerance of hepatocytes in vitro. Mechanistically, loss of PHD1 decreased production of oxidative stress, which likely relates to a decrease in oxygen consumption as a result of a reprogramming of hepatocellular metabolism. Conclusions: Loss of PHD1 provided tolerance of hepatocytes to acute hypoxia and protected them against I/R-damage. Short-term inhibition of PHD1 is a novel therapeutic approach to reducing or preventing I/R-induced liver injury.Funding supported by the Emmy Noether-Program of the Deutsche Forschungsgemeinschaft (to MS), by grant IUAP06/30 from the Federal Government Belgium and by grants FWO G.0265 and FWO G.0387 from the Flanders Research Foundation, Belgium.ElsevierCiencias de la SaludOsasun Zientziak2010info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2454/56174reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglés© 2010 Elsevier Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/561742026-06-17T12:41:47Z
dc.title.none.fl_str_mv Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
title Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
spellingShingle Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
Schneider, Martin
PHD1
Prolyl hydroxylase
Ischemia/Reperfusion
title_short Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
title_full Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
title_fullStr Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
title_full_unstemmed Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
title_sort Loss or silencing of the PHD1 prolyl hydroxylase protects livers of mice against ischemia/reperfusion injury
dc.creator.none.fl_str_mv Schneider, Martin
Van Geyte, Katie
Fraisl, Peter
Kiss, Judit
Aragonés, Julián
Mazzone, Massimiliano
Mairbäurl, Heimo
De Bock, Katrien
Ho Jeoung, Nam
Mollenhauer, Martin
Georgiadou, Maria
Bishop, Tammie
Roncal Mancho, Carmen
Sutherland, Andrew
Jordan, Benedicte
Gallez, Bernard
Weitz, Jürgen
Harris, Robert A.
Maxwell, Patrick
Baes, Myriam
Ratcliffe, Peter
Carmeliet, Peter
author Schneider, Martin
author_facet Schneider, Martin
Van Geyte, Katie
Fraisl, Peter
Kiss, Judit
Aragonés, Julián
Mazzone, Massimiliano
Mairbäurl, Heimo
De Bock, Katrien
Ho Jeoung, Nam
Mollenhauer, Martin
Georgiadou, Maria
Bishop, Tammie
Roncal Mancho, Carmen
Sutherland, Andrew
Jordan, Benedicte
Gallez, Bernard
Weitz, Jürgen
Harris, Robert A.
Maxwell, Patrick
Baes, Myriam
Ratcliffe, Peter
Carmeliet, Peter
author_role author
author2 Van Geyte, Katie
Fraisl, Peter
Kiss, Judit
Aragonés, Julián
Mazzone, Massimiliano
Mairbäurl, Heimo
De Bock, Katrien
Ho Jeoung, Nam
Mollenhauer, Martin
Georgiadou, Maria
Bishop, Tammie
Roncal Mancho, Carmen
Sutherland, Andrew
Jordan, Benedicte
Gallez, Bernard
Weitz, Jürgen
Harris, Robert A.
Maxwell, Patrick
Baes, Myriam
Ratcliffe, Peter
Carmeliet, Peter
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ciencias de la Salud
Osasun Zientziak
dc.subject.none.fl_str_mv PHD1
Prolyl hydroxylase
Ischemia/Reperfusion
topic PHD1
Prolyl hydroxylase
Ischemia/Reperfusion
description Background & Aims: Liver ischemia/reperfusion (I/R) injury is a frequent cause of organ dysfunction. Loss of the oxygen sensor prolyl hydroxylase domain enzyme 1 (PHD1) causes tolerance of skeletal muscle to hypoxia. We assessed whether loss or short-term silencing of PHD1 could likewise induce hypoxia tolerance in hepatocytes and protect them against hepatic I/R damage. Methods: Hepatic ischemia was induced in mice by clamping of the portal vessels of the left lateral liver lobe; 90 minutes later livers were reperfused for 8 hours for I/R experiments. Hepatocyte damage following ischemia or I/R was investigated in PHD1-deficient (PHD1-/-) and wild-type mice or following short hairpin RNA-mediated short-term inhibition of PHD1 in vivo. Results: PHD1-/- livers were largely protected against acute ischemia or I/R injury. Among mice subjected to hepatic I/R followed by surgical resection of all nonischemic liver lobes, more than half of wild-type mice succumbed, whereas all PHD1-/- mice survived. Also, short-term inhibition of PHD1 through RNA interference-mediated silencing provided protection against I/R. Knockdown of PHD1 also induced hypoxia tolerance of hepatocytes in vitro. Mechanistically, loss of PHD1 decreased production of oxidative stress, which likely relates to a decrease in oxygen consumption as a result of a reprogramming of hepatocellular metabolism. Conclusions: Loss of PHD1 provided tolerance of hepatocytes to acute hypoxia and protected them against I/R-damage. Short-term inhibition of PHD1 is a novel therapeutic approach to reducing or preventing I/R-induced liver injury.
publishDate 2010
dc.date.none.fl_str_mv 2010
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2454/56174
url https://hdl.handle.net/2454/56174
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv © 2010 Elsevier Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv © 2010 Elsevier Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
instname:Universidad Pública de Navarra
instname_str Universidad Pública de Navarra
reponame_str Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
collection Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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