{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T13:49:40Z","timestamp":1782827380024,"version":"3.54.5"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"25","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,6,23]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Atrial fibrillation (AF) is the most common arrhythmia and is associated with high morbidity and mortality, particularly in the aging population. Current treatment and prevention strategies remain suboptimal, highlighting the urgent need to better understand the mechanisms underlying aging-associated AF. We recently reported a causal role of the stress-activated kinase JNK2 (c-Jun N-terminal kinase 2) in aging-associated AF pathogenesis, mediated by JNK2-driven sarcoplasmic reticulum Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      dysfunction. However, the mechanisms by which cardiac JNK2 is activated during aging to promote AF remain unclear. Emerging evidence suggests that interorgan crosstalk contributes critically to the development of cardiovascular diseases. A hyperpermeable gastrointestinal epithelial barrier (\u201cleaky gut\u201d), commonly observed in aged individuals, is associated with elevated levels of proinflammatory cytokines and an increased risk of AF. Although proinflammatory cytokines have been proposed as predisposing factors for AF, clinical and experimental studies have yielded inconsistent results, underscoring the complexity of inflammation-associated AF pathogenesis. Here, we investigated whether cardiac JNK2 integrates diverse stress stimuli, including proinflammatory cytokines and lipopolysaccharide, to drive AF pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We used aged mice, intestinal epithelium\u2013specific tight junction OD (occludin) knockdown (OD\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      ) mice, and a well-established dextran sulfate sodium\u2013induced leaky gut mouse model characterized by reduced gastrointestinal epithelial occludin expression. A series of physiological and molecular approaches was applied to assess cardiac and gastrointestinal responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We found that leaky gut significantly activates atrial JNK2, which, in turn, drives Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      -triggered arrhythmic activity and increases AF inducibility in aged, dextran sulfate sodium\u2013treated, and OD\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                      mouse models. Restoration of gut barrier function in dextran sulfate sodium mice, a clinically relevant model, reduced AF susceptibility. Similarly, either JNK2 inhibition or TNF-\u03b1 (tumor necrosis factor \u03b1) blockade abolished the increased AF risk associated with leaky gut. Furthermore, we demonstrate, for the first time, that leaky gut\u2013associated proinflammatory cytokines, including TNF-\u03b1 and IL-17A (interleukin-17A), together with lipopolysaccharide, activate cardiac JNK2. This activation promotes AF pathogenesis through JNK2-mediated arrhythmogenic mechanisms, including diastolic sarcoplasmic reticulum Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      leak, Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      waves, and delayed afterdepolarizations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Activated JNK2 functions as a pathological nodal integrator of leaky gut\u2013associated stress signals, mediating gut-to-heart crosstalk and driving inflammation-induced AF pathogenesis. Targeting JNK2 may represent a novel therapeutic strategy for AF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.076147","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:00:19Z","timestamp":1776675619000},"page":"2029-2043","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["JNK2 Is a Stress Integrator Driving Atrial Fibrillation Pathogenesis in Aging via Gut-Heart Crosstalk"],"prefix":"10.1161","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-7175","authenticated-orcid":true,"given":"Jiajie","family":"Yan","sequence":"first","affiliation":[{"name":"Departments of Physiology and Cell Biology (J.Y., A.K., S.K., N.R., X.W., A.R., I.D., D.J.B., X.A.), The Ohio State University, Columbus, OH."},{"name":"Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL (J.Y., E.C., J.D., M.Y., J.R., D.J.B., X.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Carrillo","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL (J.Y., E.C., J.D., M.Y., J.R., D.J.B., X.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4430-6756","authenticated-orcid":true,"given":"Aaryan","family":"Kohli","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Cell Biology (J.Y., A.K., S.K., N.R., X.W., A.R., I.D., D.J.B., X.A.), The Ohio State University, Columbus, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8860-7389","authenticated-orcid":true,"given":"Saugat","family":"Khanal","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Cell Biology (J.Y., A.K., S.K., N.R., X.W., A.R., I.D., D.J.B., X.A.), The Ohio State University, Columbus, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1019-3834","authenticated-orcid":true,"given":"Nikola","family":"Ricchiuti","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Cell Biology (J.Y., A.K., S.K., N.R., X.W., A.R., I.D., D.J.B., X.A.), The Ohio State University, Columbus, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"DeSantiago","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, Rush University Medical Center, Chicago, IL (J.Y., E.C., J.D., M.Y., J.R., D.J.B., X.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0417-3437","authenticated-orcid":true,"given":"Xiaoping","family":"Wan","sequence":"additional","affiliation":[{"name":"Departments of Physiology and Cell Biology (J.Y., A.K., S.K., N.R., X.W., A.R., I.D., D.J.B., X.A.), The Ohio State University, Columbus, OH."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5237-8397","authenticated-orcid":true,"given":"Mei","family":"Han","sequence":"additional","affiliation":[{"name":"Internal Medicine (M.H., T.J.H.), The Ohio State University, Columbus, OH."},{"name":"Dorothy M. 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