{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T03:56:21Z","timestamp":1788494181880,"version":"build-2803163510"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL151924"],"award-info":[{"award-number":["HL151924"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL45095"],"award-info":[{"award-number":["HL45095"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute for General Medical Sciences","doi-asserted-by":"crossref","award":["GM135399"],"award-info":[{"award-number":["GM135399"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000057","name":"National Institute for General Medical Sciences","doi-asserted-by":"crossref","award":["1-S10-OD032249-01"],"award-info":[{"award-number":["1-S10-OD032249-01"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Activation of the transcriptional factor Kr\u00fcppel-like factor 5 (KLF5) is detrimental to chronic heart failure. We explored the involvement of KLF5 in myocardial ischaemia\/reperfusion injury.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Yorkshire pigs underwent 75\u2032 of ischaemia, followed by 3 or 24\u2005h of reperfusion. C57BL\/6J mice underwent 30\u2032 of ischaemia, followed by 10\u2032, 2, 12, 24\u2005h, or 4 weeks of reperfusion. Hearts and isolated cardiomyocytes (CMs) were analysed for gene expression. We assessed cardiac function, infarct size (IS), oxidative stress, and fibrosis in mice subjected to pharmacologic or genetic KLF5 inhibition, as well as pharmacologic inhibition of NADPH oxidases or glucose transporter (GLUT)1 and GLUT4. Bulk RNA sequencing, untargeted 1H-NMR metabolomics, and LC\u2013MS lipidomics were performed. Isolated primary murine CMs were infected with recombinant adenovirus expressing KLF5. During reperfusion, CM KLF5 expression was increased in porcine and murine hearts. Pharmacologic or CM-specific genetic inhibition of KLF5 reduced IS and improved cardiac function in mice. Importantly, acute KLF5 inhibition during early reperfusion suppressed fibrosis and preserved systolic cardiac function 4 weeks post-ischaemia\/reperfusion. This improvement was associated with lower NADPH-oxidase 4 (NOX4) expression, less oxidative stress, and suppressed inflammation and cell apoptosis. Pharmacologic inhibition of NOX4 conferred the same benefit. Metabolomic analysis indicated that KLF5 inhibition lowered glucose-derived metabolites (UDP-glucose and lactate) at early reperfusion. Accordingly, cardiac GLUT1 and GLUT4 levels were increased with ischaemia\/reperfusion, which was reverted by KLF5 inhibition. Pharmacologic inhibition of both GLUT1 and GLUT4 reduced IS. Finally, myocardial KLF5 overexpression increased GLUT1 mRNA levels and mouse mortality.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Ischaemia\/reperfusion increases CM KLF5 expression in pigs and mice. This constitutes a central element of myocardial injury pathophysiology and is associated with stimulation of GLUT1 and GLUT4 expression, activation of NOX4, oxidative stress, inflammation, and apoptosis. Acute KLF5 inhibition during reperfusion constitutes a novel therapeutic approach against myocardial ischaemia\/reperfusion injury.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf040","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T10:43:49Z","timestamp":1741862629000},"page":"900-914","source":"Crossref","is-referenced-by-count":7,"title":["Cardiac ischaemia\/reperfusion in pigs and mice increases cardiomyocyte Kr\u00fcppel-like factor 5 that aggravates tissue injury and remodelling"],"prefix":"10.1093","volume":"121","author":[{"given":"Nikolaos","family":"Mylonas","sequence":"first","affiliation":[{"name":"Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine , 231 Albert Sabin Way, CVC-5939, Cincinnati, OH 45267 ,","place":["USA"]},{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens , Panepistimioupolis, Zografou, Athens 15771 ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Siokatas","sequence":"additional","affiliation":[{"name":"Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine , 231 Albert Sabin Way, CVC-5939, Cincinnati, OH 45267 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Effimia","family":"Zacharia","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University , 3500 N. Broad St., Philadelphia, PA 19140 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Pol","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University , 3500 N. Broad St., Philadelphia, PA 19140 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Rolland","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, The Clinical and Translational Research Center of the University at Buffalo , 875 Ellicott St., Buffalo, NY 14203 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis D","family":"Kyriazis","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University , 3500 N. Broad St., Philadelphia, PA 19140 ,","place":["USA"]},{"name":"Laboratory of Pharmacology, Faculty of Medicine, University of Thessaly , Larissa 41500 ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University , 3500 N. Broad St., Philadelphia, PA 19140 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alycia","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University , 3500 N. Broad St., Philadelphia, PA 19140 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bannister","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology , 120 Scripps Way, Jupiter, FL 33458 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erhe","family":"Gao","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University , 3500 N. Broad St., Philadelphia, PA 19140 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ira J","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Grossman School of Medicine , 550 1st Ave., New York, NY 10016 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent W","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renaissance School of Medicine, Stony Brook University , 100 Nicolls Rd, Stony Brook, NY 11794 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka B","family":"Bialkowska","sequence":"additional","affiliation":[{"name":"Department of Medicine, Renaissance School of Medicine, Stony Brook University , 100 Nicolls Rd, Stony Brook, NY 11794 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W","family":"Elrod","sequence":"additional","affiliation":[{"name":"Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine at Temple University , 3500 N. Broad St., Philadelphia, PA 19140 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"John M","family":"Canty","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, The Clinical and Translational Research Center of the University at Buffalo , 875 Ellicott St., Buffalo, NY 14203 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Andreadou","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens , Panepistimioupolis, Zografou, Athens 15771 ,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Weil","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, The Clinical and Translational Research Center of the University at Buffalo , 875 Ellicott St., Buffalo, NY 14203 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0903-834X","authenticated-orcid":false,"given":"Konstantinos","family":"Drosatos","sequence":"additional","affiliation":[{"name":"Metabolic Biology Laboratory, Cardiovascular Center, Department of Pharmacology, Physiology, and Neurobiology, University of Cincinnati College of Medicine , 231 Albert Sabin Way, CVC-5939, Cincinnati, OH 45267 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,3,13]]},"reference":[{"key":"2025061210322907800_cvaf040-B1","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/S0140-6736(20)30925-9","article-title":"Global burden of 369 diseases and injuries in 204 countries and territories, 1990\u20132019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"396","author":"Vos","year":"2020","journal-title":"Lancet"},{"key":"2025061210322907800_cvaf040-B2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.medj.2023.12.007","article-title":"Myocardial ischemia\/reperfusion: translational pathophysiology of ischemic heart disease","volume":"5","author":"Heusch","year":"2024","journal-title":"Med"},{"key":"2025061210322907800_cvaf040-B3","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41569-020-0403-y","article-title":"Myocardial ischaemia\u2013reperfusion injury and cardioprotection in perspective","volume":"17","author":"Heusch","year":"2020","journal-title":"Nat Rev Cardiol"},{"key":"2025061210322907800_cvaf040-B4","doi-asserted-by":"crossref","DOI":"10.1177\/10742484231179613","article-title":"Cardioprotection and its translation: a need for new paradigms? 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