| First Author | Romero-Becerra R | Year | 2022 |
| Journal | Elife | Volume | 11 |
| PubMed ID | 35971771 | Mgi Jnum | J:328707 |
| Mgi Id | MGI:7332465 | Doi | 10.7554/eLife.75250 |
| Citation | Romero-Becerra R, et al. (2022) MKK6 deficiency promotes cardiac dysfunction through MKK3-p38gamma/delta-mTOR hyperactivation. Elife 11:e75250 |
| abstractText | 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 (p38alpha, p38beta, p38gamma, and p38delta) 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 p38alpha activation while causing MKK3-p38gamma/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 p38gamma or p38delta or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38gamma/delta pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38alpha inhibitors in the long-term treatment since they might result in cardiotoxicity. |
