Aging is a major risk factor for cardiac diseases, including heart failure, myocardial infarction, and arrhythmias. Activation of p38 MAPKs regulates cardiac remodeling and contributes to age-related cardiac dysfunction. However, the isoform-specific roles of p38 kinases in the aging heart remain poorly understood. Although p38{beta} has been reported to exert cardioprotective effects in models of doxorubicin-induced cardiotoxicity and ischemia-reperfusion, its role in cardiac aging remains unclear. Here, we investigated the role of p38{beta} using p38{beta} germline knockout (p38{beta}-/-) mice. Aged p38{beta}-/- mice exhibited increased LV hypertrophy, QT prolongation, calcium mishandling, heightened susceptibility to arrhythmias, increased myocardial fibrosis, and an altered inflammatory microenvironment, compared with age-matched wild-type controls. Transcriptomic profiling revealed that p38{beta} deletion reprograms the cardiac transcriptome in aged mice, suppressing innate immune and proteostasis-related pathways while promoting adaptive immune activation, developmental, extracellular vesicle-mediated, and ion-transport pathways. Collectively, these findings identify p38{beta} as a critical regulator of structural, electrophysiological, and immune homeostasis in the aging heart and demonstrate that its loss promotes maladaptive remodeling and arrhythmogenic vulnerability.
Trampel, K., Salman, B., Leoni, L., Green, S., Saleem, N., Adli, A., Procissi, D., Efimov, I., Efimova, T.
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