MKK6 deficiency promotes cardiac dysfunction through MKK3-p38 gamma/delta-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 (p38 alpha, p38 beta, p38 gamma, and p38 delta) 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 p38 alpha activation while causing MKK3-p38 gamma/delta 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 p38 gamma or p38 delta or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38 gamma/delta pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38 alpha inhibitors in the long-term treatment since they might result in cardiotoxicity.