GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.

Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. Mice were irradiated...

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Autores: Takaoka, Minoru, Tadross, John A, Al-Hadithi, Ali B A K, Zhao, Xiaohui, Villena-Gutiérrez, Rocío, Tromp, Jasper, Absar, Shazia, Au, Marcus, Harrison, James, Coll, Anthony P, Marciniak, Stefan J, Rimmington, Debra, Oliver, Eduardo, Ibáñez, Borja, Voors, Adriaan A, O'Rahilly, Stephen, Mallat, Ziad, Goodall, Jane C
Formato: artículo
Fecha de publicación:2024
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26541
Acesso em linha:https://hdl.handle.net/20.500.12105/26541
Access Level:acceso abierto
Palavra-chave:Cachexia
GDF15
Heart failure
Integrated stress response
PPP1R15A
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spelling GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.Takaoka, MinoruTadross, John AAl-Hadithi, Ali B A KZhao, XiaohuiVillena-Gutiérrez, RocíoTromp, JasperAbsar, ShaziaAu, MarcusHarrison, JamesColl, Anthony PMarciniak, Stefan JRimmington, DebraOliver, EduardoIbáñez, BorjaVoors, Adriaan AO'Rahilly, StephenMallat, ZiadGoodall, Jane CCachexiaGDF15Heart failureIntegrated stress responsePPP1R15AHeart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.Oxford University Press20252025-03-2020242024-12-3120242024-12-31research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.12105/26541reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/265412026-06-12T12:43:37Z
dc.title.none.fl_str_mv GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
title GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
spellingShingle GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
Takaoka, Minoru
Cachexia
GDF15
Heart failure
Integrated stress response
PPP1R15A
title_short GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
title_full GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
title_fullStr GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
title_full_unstemmed GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
title_sort GDF15 antagonism limits severe heart failure and prevents cardiac cachexia.
dc.creator.none.fl_str_mv Takaoka, Minoru
Tadross, John A
Al-Hadithi, Ali B A K
Zhao, Xiaohui
Villena-Gutiérrez, Rocío
Tromp, Jasper
Absar, Shazia
Au, Marcus
Harrison, James
Coll, Anthony P
Marciniak, Stefan J
Rimmington, Debra
Oliver, Eduardo
Ibáñez, Borja
Voors, Adriaan A
O'Rahilly, Stephen
Mallat, Ziad
Goodall, Jane C
author Takaoka, Minoru
author_facet Takaoka, Minoru
Tadross, John A
Al-Hadithi, Ali B A K
Zhao, Xiaohui
Villena-Gutiérrez, Rocío
Tromp, Jasper
Absar, Shazia
Au, Marcus
Harrison, James
Coll, Anthony P
Marciniak, Stefan J
Rimmington, Debra
Oliver, Eduardo
Ibáñez, Borja
Voors, Adriaan A
O'Rahilly, Stephen
Mallat, Ziad
Goodall, Jane C
author_role author
author2 Tadross, John A
Al-Hadithi, Ali B A K
Zhao, Xiaohui
Villena-Gutiérrez, Rocío
Tromp, Jasper
Absar, Shazia
Au, Marcus
Harrison, James
Coll, Anthony P
Marciniak, Stefan J
Rimmington, Debra
Oliver, Eduardo
Ibáñez, Borja
Voors, Adriaan A
O'Rahilly, Stephen
Mallat, Ziad
Goodall, Jane C
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Cachexia
GDF15
Heart failure
Integrated stress response
PPP1R15A
topic Cachexia
GDF15
Heart failure
Integrated stress response
PPP1R15A
description Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024-12-31
2024
2024-12-31
2025
2025-03-20
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/26541
url https://hdl.handle.net/20.500.12105/26541
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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