{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T01:33:20Z","timestamp":1783388000287,"version":"3.54.6"},"reference-count":52,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000098","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AA024769"],"award-info":[{"award-number":["R01AA024769"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL168728"],"award-info":[{"award-number":["R01HL168728"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL146744"],"award-info":[{"award-number":["R01HL146744"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Long-term alcohol consumption leads to cardiac arrhythmias including atrial fibrillation (AF), the most common alcohol-related arrhythmia. While AF significantly increases morbidity and mortality in patients, it takes years for an alcoholic individual undergoing an adaptive status with normal cardiac function to reach alcoholic cardiomyopathy. The underlying mechanism remains unclear to date. In this study, we assessed the functional role of JNK2 in long-term alcohol-evoked atrial arrhythmogenicity but preserved cardiac function. Wild-type (WT) mice and cardiac-specific JNK2dn mice (with an overexpression of inactive dominant negative (dn) JNK2) were treated with alcohol (2 g\/kg daily for 2 months; 2 Mo). Confocal Ca2+ imaging in the intact mouse hearts showed that long-term alcohol prolonged intracellular Ca2+ transient decay, and increased pacing-induced Ca2+ waves, compared to that of sham controls, while cardiac-specific JNK2 inhibition in JNK2dn mice precluded alcohol-evoked Ca2+-triggered activities. Moreover, activated JNK2 enhances diastolic SR Ca2+ leak in 24 h and 48 h alcohol-exposed HL-1 atrial myocytes as well as HEK-RyR2 cells (inducible expression of human RyR2) with the overexpression of tGFP-tagged active JNK2-tGFP or inactive JNK2dn-tGFP. Meanwhile, the SR Ca2+ load and systolic Ca2+ transient amplitude were both increased in ventricular myocytes, along with the preserved cardiac function in 2 Mo alcohol-exposed mice. Moreover, the role of activated JNK2 in SR Ca2+ overload and enhanced transient amplitude was also confirmed in long-term alcohol-exposed HL-1 atrial myocytes. In conclusion, our findings suggest that long-term alcohol-activated JNK2 is a key driver in preserved cardiac function, but at the expense of enhanced cardiac arrhythmogenicity. Modulating JNK2 activity could be a novel anti-arrhythmia therapeutic strategy.<\/jats:p>","DOI":"10.3390\/cells12182233","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T07:57:17Z","timestamp":1694159837000},"page":"2233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Long-Term Alcohol-Activated c-Jun N-terminal Kinase Isoform 2 Preserves Cardiac Function but Drives Ca2+-Triggered Arrhythmias"],"prefix":"10.3390","volume":"12","author":[{"given":"Nikola","family":"Ricchiuti","sequence":"first","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine\/Wexner Medical Center, The Ohio State University, 333 W 10th Avenue, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurtis","family":"Chenoweth","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine\/Wexner Medical Center, The Ohio State University, 333 W 10th Avenue, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianlong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine\/Wexner Medical Center, The Ohio State University, 333 W 10th Avenue, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan J.","family":"Bare","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine\/Wexner Medical Center, The Ohio State University, 333 W 10th Avenue, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine\/Wexner Medical Center, The Ohio State University, 333 W 10th Avenue, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0739-0286","authenticated-orcid":false,"given":"Xun","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Physiology and Cell Biology, College of Medicine\/Wexner Medical Center, The Ohio State University, 333 W 10th Avenue, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1161\/CIRCULATIONAHA.105.595140","article-title":"Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence","volume":"114","author":"Miyasaka","year":"2006","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1001\/jama.285.18.2370","article-title":"Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study","volume":"285","author":"Go","year":"2001","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s10840-008-9337-8","article-title":"Epidemiology of atrial fibrillation","volume":"25","author":"Rich","year":"2009","journal-title":"J. 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