1. p38γ/δ activation alters cardiac electrical activity and predisposes to ventricular arrhythmia.
- Author
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Romero-Becerra R, Cruz FM, Mora A, Lopez JA, Ponce-Balbuena D, Allan A, Ramos-Mondragón R, González-Terán B, León M, Rodríguez ME, Leiva-Vega L, Guerrero-Serna G, Jimenez-Vazquez EN, Filgueiras-Rama D, Vázquez J, Jalife J, and Sabio G
- Subjects
- Animals, Action Potentials drug effects, Action Potentials physiology, Disease Models, Animal, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 13 metabolism, Mitogen-Activated Protein Kinase 13 genetics, Phosphorylation, Myocytes, Cardiac metabolism, Male, Enzyme Activation, Mice, Ventricular Premature Complexes physiopathology, Ventricular Premature Complexes genetics, Ventricular Premature Complexes metabolism, Sarcoplasmic Reticulum metabolism, Mice, Knockout, Humans, Calcium Signaling, Age Factors, Mitogen-Activated Protein Kinase 12 metabolism, Mitogen-Activated Protein Kinase 12 genetics, Ryanodine Receptor Calcium Release Channel metabolism, Ryanodine Receptor Calcium Release Channel genetics, Ventricular Fibrillation physiopathology, Ventricular Fibrillation metabolism, Ventricular Fibrillation genetics
- Abstract
Ventricular fibrillation (VF) is a leading immediate cause of sudden cardiac death. There is a strong association between aging and VF, although the mechanisms are unclear, limiting the availability of targeted therapeutic interventions. Here we found that the stress kinases p38γ and p38δ are activated in the ventricles of old mice and mice with genetic or drug-induced arrhythmogenic conditions. We discovered that, upon activation, p38γ and p38δ cooperatively increase the susceptibility to stress-induced VF. Mechanistically, our data indicate that activated p38γ and p38δ phosphorylate ryanodine receptor 2 (RyR2) disrupt Kv4.3 channel localization, promoting sarcoplasmic reticulum calcium leak, I
to current reduction and action potential duration prolongation. In turn, this led to aberrant intracellular calcium handling, premature ventricular complexes and enhanced susceptibility to VF. Blocking this pathway protected genetically modified animals from VF development and reduced the VF duration in aged animals. These results indicate that p38γ and p38δ are a potential therapeutic target for sustained VF prevention., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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