Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/15171
Título
MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.
Autor(es)
Romero-Becerra, Rafael | Mora, Alfonso CNIC | Manieri, Elisa CNIC | Nikolic, Ivana CNIC | Santamans, Ayelén Melina | Montalvo-Romeral, Valle CNIC | Cruz, Francisco Miguel CNIC | Rodríguez, Elena | León, Marta | Leiva-Vega, Luis CNIC | Sanz, Laura | Bondía, Víctor | Filgueiras-Rama, David CNIC | Jiménez-Borreguero, Luis Jesús | Jalife, Jose CNIC | Gonzalez-Teran, Barbara CNIC | Sabio, Guadalupe CNIC
Fecha de publicación
2022
Cita
Elife. 2022 Aug 16;11:e75250.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
MESH
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
Versión en línea
DOI
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