MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.

Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members...

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Detalles Bibliográficos
Autores: Romero-Becerra, Rafael, Mora, Alfonso, Manieri, Elisa, Nikolic, Ivana, Santamans, Ayelén Melina, Montalvo-Romeral, Valle, Cruz, Francisco Miguel, Rodríguez, Elena, León, Marta, Leiva-Vega, Luis, Sanz, Laura, Bondía, Víctor, Filgueiras-Rama, David, Jiménez-Borreguero, Luis Jesús, Jalife, Jose, Gonzalez-Teran, Barbara, Sabio, Guadalupe
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/15171
Acceso en línea:http://hdl.handle.net/20.500.12105/15171
Access Level:acceso abierto
Palabra clave:Heart Diseases
MAP Kinase Kinase 6
Mitogen-Activated Protein Kinase 13
Animals
Cardiomegaly
Longitudinal Studies
MAP Kinase Kinase 3
Mice
TOR Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/15171
network_acronym_str ES
network_name_str España
repository_id_str
spelling MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.Romero-Becerra, RafaelMora, AlfonsoManieri, ElisaNikolic, IvanaSantamans, Ayelén MelinaMontalvo-Romeral, ValleCruz, Francisco MiguelRodríguez, ElenaLeón, MartaLeiva-Vega, LuisSanz, LauraBondía, VíctorFilgueiras-Rama, DavidJiménez-Borreguero, Luis JesúsJalife, JoseGonzalez-Teran, BarbaraSabio, GuadalupeHeart DiseasesMAP Kinase Kinase 6Mitogen-Activated Protein Kinase 13AnimalsCardiomegalyLongitudinal StudiesMAP Kinase Kinase 3MiceTOR Serine-Threonine Kinasesp38 Mitogen-Activated Protein KinasesStress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.eLife Sciences PublicationsCentro Nacional de Investigaciones Cardiovasculares Carlos III (España)Ministerio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)American Heart AssociationMinisterio de Ciencia, Innovación y Universidades (España)European Foundation for the Study of DiabetesAsociación Española Contra el CáncerComunidad de Madrid (España)NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos)Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Fundación La CaixaFundación La Marató TV3Instituto de Salud Carlos IIIMarie Curie20222022-11-1620222022-01-0120222022-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/15171reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/151712026-06-12T12:43:37Z
dc.title.none.fl_str_mv MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
title MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
spellingShingle MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
Romero-Becerra, Rafael
Heart Diseases
MAP Kinase Kinase 6
Mitogen-Activated Protein Kinase 13
Animals
Cardiomegaly
Longitudinal Studies
MAP Kinase Kinase 3
Mice
TOR Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
title_short MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
title_full MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
title_fullStr MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
title_full_unstemmed MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
title_sort MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
dc.creator.none.fl_str_mv Romero-Becerra, Rafael
Mora, Alfonso
Manieri, Elisa
Nikolic, Ivana
Santamans, Ayelén Melina
Montalvo-Romeral, Valle
Cruz, Francisco Miguel
Rodríguez, Elena
León, Marta
Leiva-Vega, Luis
Sanz, Laura
Bondía, Víctor
Filgueiras-Rama, David
Jiménez-Borreguero, Luis Jesús
Jalife, Jose
Gonzalez-Teran, Barbara
Sabio, Guadalupe
author Romero-Becerra, Rafael
author_facet Romero-Becerra, Rafael
Mora, Alfonso
Manieri, Elisa
Nikolic, Ivana
Santamans, Ayelén Melina
Montalvo-Romeral, Valle
Cruz, Francisco Miguel
Rodríguez, Elena
León, Marta
Leiva-Vega, Luis
Sanz, Laura
Bondía, Víctor
Filgueiras-Rama, David
Jiménez-Borreguero, Luis Jesús
Jalife, Jose
Gonzalez-Teran, Barbara
Sabio, Guadalupe
author_role author
author2 Mora, Alfonso
Manieri, Elisa
Nikolic, Ivana
Santamans, Ayelén Melina
Montalvo-Romeral, Valle
Cruz, Francisco Miguel
Rodríguez, Elena
León, Marta
Leiva-Vega, Luis
Sanz, Laura
Bondía, Víctor
Filgueiras-Rama, David
Jiménez-Borreguero, Luis Jesús
Jalife, Jose
Gonzalez-Teran, Barbara
Sabio, Guadalupe
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Centro Nacional de Investigaciones Cardiovasculares Carlos III (España)
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
American Heart Association
Ministerio de Ciencia, Innovación y Universidades (España)
European Foundation for the Study of Diabetes
Asociación Española Contra el Cáncer
Comunidad de Madrid (España)
NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos)
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Fundación La Caixa
Fundación La Marató TV3
Instituto de Salud Carlos III
Marie Curie
dc.subject.none.fl_str_mv Heart Diseases
MAP Kinase Kinase 6
Mitogen-Activated Protein Kinase 13
Animals
Cardiomegaly
Longitudinal Studies
MAP Kinase Kinase 3
Mice
TOR Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
topic Heart Diseases
MAP Kinase Kinase 6
Mitogen-Activated Protein Kinase 13
Animals
Cardiomegaly
Longitudinal Studies
MAP Kinase Kinase 3
Mice
TOR Serine-Threonine Kinases
p38 Mitogen-Activated Protein Kinases
description Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-11-16
2022
2022-01-01
2022
2022-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
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 http://hdl.handle.net/20.500.12105/15171
url http://hdl.handle.net/20.500.12105/15171
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
Atribución 4.0 Internacional
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
Atribución 4.0 Internacional
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 eLife Sciences Publications
publisher.none.fl_str_mv eLife Sciences Publications
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
_version_ 1869423251028967424
score 15,812429

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