{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:01Z","timestamp":1787028541957,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T00:00:00Z","timestamp":1718150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["F31 HL165924"],"award-info":[{"award-number":["F31 HL165924"]}]},{"name":"National Institutes of Health","award":["R01 EY029702"],"award-info":[{"award-number":["R01 EY029702"]}]},{"name":"National Institutes of Health","award":["1-INO-2024-1538-A-N"],"award-info":[{"award-number":["1-INO-2024-1538-A-N"]}]},{"name":"National Institutes of Health","award":["11-23-PDF-84"],"award-info":[{"award-number":["11-23-PDF-84"]}]},{"name":"National Institutes of Health","award":["898925"],"award-info":[{"award-number":["898925"]}]},{"name":"Juvenile Diabetes Research Foundation Innovative Award","award":["F31 HL165924"],"award-info":[{"award-number":["F31 HL165924"]}]},{"name":"Juvenile Diabetes Research Foundation Innovative Award","award":["R01 EY029702"],"award-info":[{"award-number":["R01 EY029702"]}]},{"name":"Juvenile Diabetes Research Foundation Innovative Award","award":["1-INO-2024-1538-A-N"],"award-info":[{"award-number":["1-INO-2024-1538-A-N"]}]},{"name":"Juvenile Diabetes Research Foundation Innovative Award","award":["11-23-PDF-84"],"award-info":[{"award-number":["11-23-PDF-84"]}]},{"name":"Juvenile Diabetes Research Foundation Innovative Award","award":["898925"],"award-info":[{"award-number":["898925"]}]},{"name":"American Diabetes Association Postdoctoral Fellowship Award","award":["F31 HL165924"],"award-info":[{"award-number":["F31 HL165924"]}]},{"name":"American Diabetes Association Postdoctoral Fellowship Award","award":["R01 EY029702"],"award-info":[{"award-number":["R01 EY029702"]}]},{"name":"American Diabetes Association Postdoctoral Fellowship Award","award":["1-INO-2024-1538-A-N"],"award-info":[{"award-number":["1-INO-2024-1538-A-N"]}]},{"name":"American Diabetes Association Postdoctoral Fellowship Award","award":["11-23-PDF-84"],"award-info":[{"award-number":["11-23-PDF-84"]}]},{"name":"American Diabetes Association Postdoctoral Fellowship Award","award":["898925"],"award-info":[{"award-number":["898925"]}]},{"name":"American Heart Association Undergraduate Research Fellowship","award":["F31 HL165924"],"award-info":[{"award-number":["F31 HL165924"]}]},{"name":"American Heart Association Undergraduate Research Fellowship","award":["R01 EY029702"],"award-info":[{"award-number":["R01 EY029702"]}]},{"name":"American Heart Association Undergraduate Research Fellowship","award":["1-INO-2024-1538-A-N"],"award-info":[{"award-number":["1-INO-2024-1538-A-N"]}]},{"name":"American Heart Association Undergraduate Research Fellowship","award":["11-23-PDF-84"],"award-info":[{"award-number":["11-23-PDF-84"]}]},{"name":"American Heart Association Undergraduate Research Fellowship","award":["898925"],"award-info":[{"award-number":["898925"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activation of the transcription factor NF-\u03baB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-\u03baB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-\u03baB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-\u03baB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNF\u03b1 or hyperglycemic conditions. A similar suppressive effect on NF-\u03baB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3\u03b2. NF-\u03baB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3\u03b2 variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3\u03b2 at S9 and upregulation of IL-1\u03b2 and CCL2. Diabetic REDD1+\/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1\u2212\/\u2212 mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1\u2212\/\u2212 mice, as compared to diabetic REDD1+\/+ mice. Overall, the results support a role for REDD1 in promoting GSK3\u03b2-dependent NF-\u03baB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.<\/jats:p>","DOI":"10.3390\/ijms25126461","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T04:15:27Z","timestamp":1718165727000},"page":"6461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["REDD1 Deletion Suppresses NF-\u03baB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6904-1618","authenticated-orcid":false,"given":"Shaunaci A.","family":"Stevens","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddharth","family":"Sunilkumar","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep M.","family":"Subrahmanian","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyson L.","family":"Toro","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer","family":"Cavus","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Penn State Health Heart and Vascular Institute, Hershey S. Milton Medical Center, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efosa V.","family":"Omorogbe","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa A.","family":"Bradley","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA"},{"name":"Division of Cardiovascular Medicine, Penn State Health Heart and Vascular Institute, Hershey S. Milton Medical Center, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Dennis","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.hfc.2019.02.003","article-title":"Diabetic Cardiomyopathy: Definition, Diagnosis, and Therapeutic Implications","volume":"15","author":"Paolillo","year":"2019","journal-title":"Heart Fail. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Boyalla, V., Gallego-Colon, E., and Spartalis, M. (2023). Immunity and inflammation in cardiovascular disorders. BMC Cardiovasc. 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