PMID- 35971771 OWN - NLM STAT- MEDLINE DCOM- 20220817 LR - 20220907 IS - 2050-084X (Electronic) IS - 2050-084X (Linking) VI - 11 DP - 2022 Aug 16 TI - MKK6 deficiency promotes cardiac dysfunction through MKK3-p38gamma/delta-mTOR hyperactivation. LID - 10.7554/eLife.75250 [doi] LID - e75250 AB - 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. CI - (c) 2022, Romero-Becerra et al. FAU - Romero-Becerra, Rafael AU - Romero-Becerra R AUID- ORCID: 0000-0003-3935-2647 AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Mora, Alfonso AU - Mora A AUID- ORCID: 0000-0002-6397-4836 AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Manieri, Elisa AU - Manieri E AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Nikolic, Ivana AU - Nikolic I AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Santamans, Ayelen Melina AU - Santamans AM AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Montalvo-Romeral, Valle AU - Montalvo-Romeral V AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Cruz, Francisco Miguel AU - Cruz FM AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Rodriguez, Elena AU - Rodriguez E AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Leon, Marta AU - Leon M AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Leiva-Vega, Luis AU - Leiva-Vega L AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Sanz, Laura AU - Sanz L AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Bondia, Victor AU - Bondia V AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Filgueiras-Rama, David AU - Filgueiras-Rama D AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. AD - CIBER de Enfermedades Cardiovasculares, Madrid, Spain. AD - Hospital Clinico Universitario San Carlos, Madrid, Spain. FAU - Jimenez-Borreguero, Luis Jesus AU - Jimenez-Borreguero LJ AUID- ORCID: 0000-0001-5870-237X AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. FAU - Jalife, Jose AU - Jalife J AUID- ORCID: 0000-0003-0080-3500 AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. AD - CIBER de Enfermedades Cardiovasculares, Madrid, Spain. AD - Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, Ann Arbor, United States. FAU - Gonzalez-Teran, Barbara AU - Gonzalez-Teran B AUID- ORCID: 0000-0002-4336-8644 AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. AD - Gladstone Institutes, San Francisco, United States. FAU - Sabio, Guadalupe AU - Sabio G AUID- ORCID: 0000-0002-2822-0625 AD - Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. LA - eng GR - R01 HL122352/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220816 PL - England TA - Elife JT - eLife JID - 101579614 RN - EC 2.7.1.- (Mitogen-Activated Protein Kinase 13) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 3) RN - EC 2.7.12.2 (MAP Kinase Kinase 6) RN - EC 2.7.12.2 (Map2k3 protein, mouse) RN - EC 2.7.12.2 (Map2k6 protein, mouse) SB - IM MH - Animals MH - Cardiomegaly MH - *Heart Diseases/genetics/pathology MH - Longitudinal Studies MH - MAP Kinase Kinase 3/metabolism MH - *MAP Kinase Kinase 6/genetics MH - Mice MH - *Mitogen-Activated Protein Kinase 13/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC9381040 OAB - The human heart can increase its size to supply more blood to the body's organs. This process, called hypertrophy, can happen during exercise or be caused by medical conditions, such as high blood pressure or inherited genetic diseases. If hypertrophy is continually driven by illness, this can cause the heart to fail and no longer be able to properly pump blood around the body. For hypertrophy to happen, several molecular changes occur in the cells responsible for contracting the heart, including activation of the p38 pathway. Within this pathway is a p38 enzyme as well as a series of other proteins which are sequentially turned on in response to stress, such as inflammatory molecules or mechanical forces that alter the cell's shape. There are different types of p38 enzyme which have been linked to other diseases, making them a promising target for drug development. However, clinical trials blocking individual members of the p38 family have had disappointing results. An alternative approach is to target other proteins involved in the p38 pathway, such as MKK6, but it is not known what effect this might have. To investigate, Romero-Becerra et al. genetically modified mice to not have any MKK6 protein. As a result, these mice had a shorter lifespan, with hypertrophy developing at a young age that led to heart problems. Romero-Becerra et al. used different mice models to understand why this happened, showing that a lack of MKK6 reduces the activity of a specific member of the p38 family called p38alpha. However, this blockage boosted a different branch of the pathway which involved two other p38 proteins, p38gamma and p38delta. This, in turn, triggered another key pathway called mTOR which also promotes hypertrophy of the heart. These results suggest that drugs blocking MKK6 and p38alpha could lead to side effects that cause further harm to the heart. A more promising approach for treating hypertrophic heart conditions could be to inhibit p38gamma and/or p38delta. However, before this can be fully explored, further work is needed to generate compounds that specifically target these proteins. OABL- eng OTO - NOTNLM OT - MKK3 OT - MKK6 OT - aging OT - cardiac hypertrophy OT - cell biology OT - mTOR OT - medicine OT - mouse OT - p38 MAPK COIS- RR, AM, EM, IN, AS, VM, FC, ER, ML, LL, LS, VB, DF, LJ, JJ, BG, GS No competing interests declared EDAT- 2022/08/17 06:00 MHDA- 2022/08/18 06:00 PMCR- 2022/08/16 CRDT- 2022/08/16 03:53 PHST- 2021/11/03 00:00 [received] PHST- 2022/07/08 00:00 [accepted] PHST- 2022/08/16 03:53 [entrez] PHST- 2022/08/17 06:00 [pubmed] PHST- 2022/08/18 06:00 [medline] PHST- 2022/08/16 00:00 [pmc-release] AID - 75250 [pii] AID - 10.7554/eLife.75250 [doi] PST - epublish SO - Elife. 2022 Aug 16;11:e75250. doi: 10.7554/eLife.75250.