2026-04-23T18:42:45Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/151712024-09-27T09:11:36Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Romero-Becerra, Rafael author Mora, Alfonso author Manieri, Elisa author Nikolic, Ivana author Santamans, Ayelén Melina author Montalvo-Romeral, Valle author Cruz, Francisco Miguel author Rodríguez, Elena author León, Marta author Leiva-Vega, Luis author Sanz, Laura author Bondía, Víctor author Filgueiras-Rama, David author Jiménez-Borreguero, Luis Jesús author Jalife, Jose author Gonzalez-Teran, Barbara author Sabio, Guadalupe author 2022 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. Elife. 2022 Aug 16;11:e75250. http://hdl.handle.net/20.500.12105/15171 35971771 10.7554/eLife.75250 2050-084X eLife MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.