dc.contributor.author | Romero-Becerra, Rafael | |
dc.contributor.author | Mora, Alfonso | |
dc.contributor.author | Manieri, Elisa | |
dc.contributor.author | Nikolic, Ivana | |
dc.contributor.author | Santamans, Ayelén Melina | |
dc.contributor.author | Montalvo-Romeral, Valle | |
dc.contributor.author | Cruz, Francisco Miguel | |
dc.contributor.author | Rodríguez, Elena | |
dc.contributor.author | León, Marta | |
dc.contributor.author | Leiva-Vega, Luis | |
dc.contributor.author | Sanz, Laura | |
dc.contributor.author | Bondía, Víctor | |
dc.contributor.author | Filgueiras-Rama, David | |
dc.contributor.author | Jiménez-Borreguero, Luis Jesús | |
dc.contributor.author | Jalife, Jose | |
dc.contributor.author | Gonzalez-Teran, Barbara | |
dc.contributor.author | Sabio, Guadalupe | |
dc.date.accessioned | 2022-11-16T15:14:00Z | |
dc.date.available | 2022-11-16T15:14:00Z | |
dc.date.issued | 2022 | |
dc.identifier.citation | Elife. 2022 Aug 16;11:e75250. | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/15171 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | We thank S Bartlett and F Chanut for English editing. We are grateful to RJ Davis, A Padmanabhan, M
Costa and C López-Otín for critical reading of the manuscript. We thank Dr. RJ Davis for the MKK3 and
MKK6 KO animals and Dr. Erwin F Wagner for the p38α flox mice. We thank AC Silva (ana@anasilva
illustrations.com) for help with figure editing and design. This work was funded by a CNIC Intramural
Project Severo Ochoa (Expediente 12–2016 IGP) to GS and JJ and PID2019-104399RB-I00 funded
by MCIN/AEI/10.13039/501100011033 to GS. BGT was a fellow of FPI Severo Ochoa CNIC Program
(SVP-2013-067639) and is an American Heart Association Postdoctoral Fellow (18POST34080175).
RRB is a fellow of the FPU Program (FPU17/03847). The following grants provided additional funding:
GS is granted by funds from European Regional Development Fund (ERDF): EFSD/Lilly European
Diabetes Research Programme Dr Sabio, Fundación AECC PROYE19047SABI and Comunidad de
Madrid IMMUNOTHERCAN-CM B2017/BMD-3733; US National Heart, Lung, and Blood Institute
(R01 Grant HL122352), Fondos FEDER, Madrid, Spain, and Fundación Bancaria “La Caixa (project
HR19/52160013); Fundación La Marató TV3: Ayudas a la investigación en enfermedades raras 2020
(LA MARATO-2020); and Instituto de Salud Carlos III to JJ. IN was funded by EFSD/Lilly grants (2017
and 2019), the CNIC IPP FP7 Marie Curie Programme (PCOFUND-2012–600396), EFSD Rising Star
award (2019), JDC-2018-Incorporación (MIN/JDC1802). The CNIC is supported by the Instituto de
Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | eLife Sciences Publications | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Heart Diseases | es_ES |
dc.subject.mesh | MAP Kinase Kinase 6 | es_ES |
dc.subject.mesh | Mitogen-Activated Protein Kinase 13 | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Cardiomegaly | es_ES |
dc.subject.mesh | Longitudinal Studies | es_ES |
dc.subject.mesh | MAP Kinase Kinase 3 | es_ES |
dc.subject.mesh | Mice | es_ES |
dc.subject.mesh | TOR Serine-Threonine Kinases | es_ES |
dc.subject.mesh | p38 Mitogen-Activated Protein Kinases | es_ES |
dc.title | MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.pubmedID | 35971771 | es_ES |
dc.format.volume | 11 | es_ES |
dc.identifier.doi | 10.7554/eLife.75250 | es_ES |
dc.contributor.funder | Centro Nacional de Investigaciones Cardiovasculares Carlos III (España) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Agencia Estatal de Investigación (España) | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.contributor.funder | American Heart Association | es_ES |
dc.contributor.funder | Ministerio de Ciencia, Innovación y Universidades (España) | es_ES |
dc.contributor.funder | European Foundation for the Study of Diabetes | es_ES |
dc.contributor.funder | Asociación Española Contra el Cáncer | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos) | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.contributor.funder | Fundación La Caixa | es_ES |
dc.contributor.funder | Fundación La Marató TV3 | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Marie Curie | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 2050-084X | es_ES |
dc.relation.publisherversion | 10.7554/eLife.75250 | es_ES |
dc.identifier.journal | eLife | es_ES |
dc.repisalud.orgCNIC | Papel de las quinasas activadas por el estrés en el desarrollo de enfermedades cardiovasculares, diabetes y cáncer | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/12–2016IGP | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-104399RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/AEI/10.13039/501100011033 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SVP-2013-067639 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/FPU17/03847 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PROYE19047SABI | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MMUNOTHERCAN-CMB2017/BMD-3733 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/HR19/52160013 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MIN/JDC1802 | es_ES |