title: The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells.
abstract: Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, thus suggesting that additional transcription factors are regulating PDK4. Interestingly, a recent study has demonstrated that the transcription factor E2F1, which is crucial for cell cycle control, may regulate PDK4 expression. Given that NF-κB may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-κB can downregulate PDK4 expression in human cardiac AC16 cells through E2F1 inhibition. Protein coimmunoprecipitation indicated that PDK4 downregulation entailed enhanced physical interaction between the p65 subunit of NF-κB and E2F1. Chromatin immunoprecipitation analyses demonstrated that p65 translocation into the nucleus prevented the recruitment of E2F1 to the PDK4 promoter and its subsequent E2F1-dependent gene transcription. Interestingly, the NF-κB inhibitor parthenolide prevented the inhibition of E2F1, while E2F1 overexpression reduced interleukin expression in stimulated cardiac cells. Based on these findings, we propose that NF-κB acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBERDEM, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.forename: David
authors.initials: D
authors.lastname: Álvarez-Guardia
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.forename: Tung O
authors.initials: TO
authors.lastname: Chan
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016328:NF-kappa B; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D005947:Glucose