{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:30:09Z","timestamp":1790613009858,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,7,13]],"date-time":"2024-07-13T00:00:00Z","timestamp":1720828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL063705"],"award-info":[{"award-number":["R01 HL063705"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01GM066730"],"award-info":[{"award-number":["P01GM066730"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL122309"],"award-info":[{"award-number":["R01 HL122309"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL152712"],"award-info":[{"award-number":["R01 HL152712"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008982","name":"National Science Foundation","doi-asserted-by":"publisher","award":["81770831"],"award-info":[{"award-number":["81770831"]}],"id":[{"id":"10.13039\/501100008982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008982","name":"National Science Foundation","doi-asserted-by":"publisher","award":["931252"],"award-info":[{"award-number":["931252"]}],"id":[{"id":"10.13039\/501100008982","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008982","name":"National Science Foundation","doi-asserted-by":"publisher","award":["FC930151"],"award-info":[{"award-number":["FC930151"]}],"id":[{"id":"10.13039\/501100008982","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Surgery at Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, USA"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia\/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-\u03b1) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-\u03b1 production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db\/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-\u03b1, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-\u03b1 levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic\/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia\/reoxygenation injury in the presence of high glucose. Hypoxia\/reoxygenation augmented HDAC6 activity and TNF-\u03b1 levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-\u03b1\u2013induced mitochondrial injury in experimental diabetes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvae144","type":"journal-article","created":{"date-parts":[[2024,7,13]],"date-time":"2024-07-13T14:05:42Z","timestamp":1720879542000},"page":"1456-1471","source":"Crossref","is-referenced-by-count":15,"title":["Genetic deletion or pharmacologic inhibition of histone deacetylase 6 protects the heart against ischaemia\/reperfusion injury by limiting tumour necrosis factor alpha\u2013induced mitochondrial injury in experimental diabetes"],"prefix":"10.1093","volume":"120","author":[{"given":"Shelley L","family":"Baumgardt","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuebin","family":"Fu","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6844-5928","authenticated-orcid":false,"given":"Zhengyuan","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University , Zhanjiang, Guangdong Province ,","place":["The People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University , 300 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachana","family":"Mishra","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthukumar","family":"Gunasekaran","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Progyaparamita","family":"Saha","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M","family":"Forbess","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeljko J","family":"Bosnjak","sequence":"additional","affiliation":[{"name":"Department of Medicine, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]},{"name":"Department of Physiology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amadou K S","family":"Camara","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy R","family":"Kersten","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward B","family":"Thorp","sequence":"additional","affiliation":[{"name":"Department of Pathology, Feinberg School of Medicine, Northwestern University , 300 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 300 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunjay","family":"Kaushal","sequence":"additional","affiliation":[{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-0846","authenticated-orcid":false,"given":"Zhi-Dong","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical College of Wisconsin , 8701 Watertown Plank Road, Milwaukee, WI 53206 ,","place":["USA"]},{"name":"Cardiovascular-Thoracic Surgery and the Heart Center, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Feinberg School of Medicine, Northwestern University , 303 E. Superior Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Pediatrics, Feinberg School of Medicine, Northwestern University , 225 E. Chicago Avenue, Chicago, IL 60611 ,","place":["USA"]},{"name":"Department of Surgery, Feinberg School of Medicine, Northwestern University , 225 E. 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