{"doi":"10.3390/ijms25126461","title":"REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice","abstract":"Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB 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-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3β. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3β variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3β at S9 and upregulation of IL-1β and CCL2. Diabetic REDD1+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1−/− mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1−/− mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3β-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.","journal":"International Journal of Molecular Sciences","year":2024,"id":456005,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9402,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":452862,"name":"Siddharth Sunilkumar","orcid":"0000-0003-3271-932X","position":1,"is_corresponding":false},{"id":890383,"name":"Sandeep Subrahmanian","orcid":"0000-0001-6462-8428","position":2,"is_corresponding":false},{"id":453863,"name":"Allyson L. Toro","orcid":null,"position":3,"is_corresponding":false},{"id":724648,"name":"Omer Cavus","orcid":"0000-0002-2930-3975","position":4,"is_corresponding":false},{"id":1280914,"name":"Efosa V. Omorogbe","orcid":null,"position":5,"is_corresponding":false},{"id":385845,"name":"Elisa A. Bradley","orcid":"0000-0003-1479-2988","position":6,"is_corresponding":false},{"id":452865,"name":"Michael D. Dennis","orcid":"0000-0002-0645-6864","position":7,"is_corresponding":false},{"id":452863,"name":"Shaunaci A. Stevens","orcid":"0000-0001-6904-1618","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:03:27.785212Z","pmid":"38928166","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}