MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
Authors: Romero-Becerra Rafael , Mora Alfonso , Manieri Elisa , Sanz Laura , Nikolic Ivana , Santamans Ayelén M. , Montalvo-Romeral Valle , Cruz Uréndez Francisco Miguel , Rodríguez Maria Elena , Leiva-Vega Luis , Bondía Víctor , Filgueiras-Rama David , Jiménez-Borreguero Luis Jesús , Jalife José , González-Terán Bárbara , Sabio Guadalupe 
Published: November 2021

Stress-activated p38 kinases control a plethora of functions and their dysregulation has been linked to 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 life span in mice. Longitudinal study of cardiac function in Mkk6-/- mice showed that young mice have 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 mTOR signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in Mkk6-/- mice is reverted by knocking out either p38γ or p38δ, or by inhibiting 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.

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