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p38β/MAPK11 Deficiency Exacerbates Cardiac Structural and Electrophysiological Remodeling and Contributes to Immune
Insights
Loss of p38β kinase in aging hearts disrupts cardiac structure, electrical function, and immune balance. This study reveals p38β
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Aging Research
Background:
- Aging is a primary risk factor for cardiac diseases.
- p38 MAPKs (mitogen-activated protein kinases) influence cardiac remodeling and dysfunction.
- Isoform-specific roles of p38 kinases in cardiac aging are not well understood.
Purpose of the Study:
- To investigate the role of p38β kinase in the aging heart.
- To determine the consequences of p38β loss on cardiac structure, electrophysiology, and immune function in aged mice.
Main Methods:
- Utilized p38β germline knockout (p38β-/-) mice.
- Compared aged p38β-/- mice with age-matched wild-type controls.
- Performed transcriptomic profiling to analyze gene expression changes.
Main Results:
- Aged p38β-/- mice showed increased left ventricular hypertrophy, QT prolongation, and calcium mishandling.
- Loss of p38β heightened susceptibility to arrhythmias, myocardial fibrosis, and altered inflammatory environment.
- Transcriptomic analysis revealed reprogramming of cardiac pathways, including immune and proteostasis regulation.
Conclusions:
- p38β is a critical regulator of structural, electrophysiological, and immune homeostasis in the aging heart.
- Loss of p38β promotes maladaptive cardiac remodeling and arrhythmogenic vulnerability.
- Isoform-specific p38 signaling is crucial; broad targeting of p38 MAPKs may have adverse effects in cardiovascular diseases.
Abstract:
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 p38β 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 p38β using p38β germline knockout (p38β -/- ) mice. Aged p38β -/- 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 p38β 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 p38β 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.
New And Noteworthy:
We identify p38β as a previously unrecognized regulator of cardiac aging. Systemic loss of p38β disrupts structural, electrophysiological, and immune homeostasis in the aging heart, revealing its protective role in maintaining cardiac function with age. These findings underscore the importance of isoform-specific p38 signaling and suggest that broadly targeting p38 MAPKs may have unintended consequences in age-related cardiovascular diseases.
