The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells.

Authors

Xavier Palomer, Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBERDEM, Faculty of Pharmacy, University of Barcelona, Barcelona, SpainFollow
David Álvarez-Guardia, 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
Mercy M Davidson, Department of Radiation Oncology, Columbia University, New York, New YorkFollow
Tung O Chan, Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Arthur M Feldman, Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PennsylvaniaFollow
Manuel Vázquez-Carrera, Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBERDEM, Faculty of Pharmacy, University of Barcelona, Barcelona, SpainFollow

Document Type

Article

Publication Date

5-1-2011

Comments

This article has been peer reviewed and is published in PLoS One 2011, 6(5). The published version is available at DOI: 10.1371/journal.pone.0019724. © Public Library of Science

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.

Recommended Citation

Palomer, Xavier; Álvarez-Guardia, David; Davidson, Mercy M; Chan, Tung O; Feldman, Arthur M; and Vázquez-Carrera, Manuel, "The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells." (2011). Department of Medicine Faculty Papers. Paper 67.
https://jdc.jefferson.edu/medfp/67

PubMed ID

21625432