{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:25:46Z","timestamp":1790717146045,"version":"4.1.0"},"reference-count":61,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100024583","name":"Medizinische Fakult\u00c3\u00a4t, Universit\u00c3\u00a4t zu K\u00c3\u00b6ln","doi-asserted-by":"publisher","award":["105\/2023"],"award-info":[{"award-number":["105\/2023"]}],"id":[{"id":"10.13039\/501100024583","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Cardiac ischemia reperfusion (I\/R) injury is a serious consequence of reperfusion therapy for myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the citrullination of proteins. In previous studies, PAD4 inhibition protected distinct organs from I\/R injury by preventing the formation of neutrophil extracellular traps (NETs) and attenuating inflammatory responses. Here, we hypothesized that cardiomyocyte PAD4 expression may play a role in acute I\/R injury.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Infarct size was determined in isolated pressure constant-perfused hearts from WT and PAD4-deficient (PAD4<jats:sup>-\/-<\/jats:sup>) mice. Additionally, extracellular reactive oxygen species (ROS) and cell viability were quantified in freshly isolated adult cardiomyocytes exposed to hypoxia followed by reoxygenation (H\/R). Resistance to oxidative stress was proven in both genotypes by treatment of neonatal cardiomyocytes with hydrogen peroxide. Moreover, intracellular ROS formation, ATP production, mitochondrial membrane polarisation, caspase-3 activation, and cell viability were quantified after hypoxia followed by 4\u2009h and 20\u2009h of reoxygenation, respectively. The PAD4-specific inhibitor GSK484 was added before H\/R or at reperfusion in certain experiments.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Infarct size was smaller in PAD4<jats:sup>-\/-<\/jats:sup> hearts following I\/R when compared to the WT. Similarly, the viability of adult and neonatal PAD4<jats:sup>-\/-<\/jats:sup> cardiomyocytes was better preserved after H\/R, accompanied by reduced ROS formation. PAD4 deficiency maintained mitochondrial integrity and protected neonatal cardiomyocytes against apoptosis. However, these cells did not exhibit resistance to hydrogen peroxide-induced cell death, indicating an unaltered antioxidative state. Whereas pharmacological PAD4 inhibition by GSK484 before H\/R sustained intracellular ATP levels in WT cardiomyocytes, administration of GSK484 at reoxygenation did not. However, GSK484 significantly improved cardiomyocyte metabolic activity, regardless of the time of administration.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Our study is the first to demonstrate that PAD4 expression in cardiomyocytes contributes to H\/R injury independent of systemic immune responses and NETs. Consequently, PAD4 may serve as a therapeutic target to alleviate I\/R injury.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0330864","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:30:37Z","timestamp":1757525437000},"page":"e0330864","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Peptidylarginine deiminase 4 deficiency alleviates hypoxia\/reoxygenation-induced cardiomyocyte injury"],"prefix":"10.1371","volume":"20","author":[{"given":"Matthias","family":"Mand","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Holthaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut 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