{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T06:50:49Z","timestamp":1782370249644,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,23]]},"group-title":"Physiology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Institutes of Health\/National Heart, Lung, and Blood Institute","award":["R01HL165002 (to I.R.E.)"],"award-info":[{"award-number":["R01HL165002 (to I.R.E.)"]}]},{"name":"NIH Physical Genomics Training Program","award":["T32GM142604 (to K.A.T.)"],"award-info":[{"award-number":["T32GM142604 (to K.A.T.)"]}]},{"name":"the Leducq Foundation grant Bioelectronics for Neurocardiology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  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\u03b2 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\u03b2 using p38\u03b2 germline knockout (p38\u03b2\n                  <jats:sup>-\/-<\/jats:sup>\n                  ) mice. Aged p38\u03b2\n                  <jats:sup>-\/-<\/jats:sup>\n                  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\u03b2 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\u03b2 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.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>NEW AND NOTEWORTHY<\/jats:title>\n                  <jats:p>We identify p38\u03b2 as a previously unrecognized regulator of cardiac aging. Systemic loss of p38\u03b2 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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.18.733182","type":"posted-content","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T22:30:23Z","timestamp":1782253823000},"source":"Crossref","is-referenced-by-count":0,"title":["p38\u03b2\/MAPK11 Deficiency Exacerbates Cardiac Structural and Electrophysiological Remodeling and Contributes to Immune Dysregulation in the Aging Heart"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5735-1037","authenticated-orcid":false,"given":"Katy A.","family":"Trampel","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Northwestern University, Chicago, IL, 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0666-7513","authenticated-orcid":false,"given":"Batool","family":"Salman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Northwestern University, Chicago, IL, 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5369-4525","authenticated-orcid":false,"given":"Lara","family":"Leoni","sequence":"additional","affiliation":[{"name":"Department of Radiology, Northwestern University, Chicago, IL, 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Northwestern University, Chicago, IL, 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noor","family":"Saleem","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, 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