| First Author | Palomer X | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 5 | Pages | e19724 |
| PubMed ID | 21625432 | Mgi Jnum | J:172724 |
| Mgi Id | MGI:5008670 | Doi | 10.1371/journal.pone.0019724 |
| Citation | Palomer X, et al. (2011) The Interplay between NF-kappaB and E2F1 Coordinately Regulates Inflammation and Metabolism in Human Cardiac Cells. PLoS One 6(5):e19724 |
| abstractText | Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-kappaB (NF-kappaB) 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-alpha (ERRalpha) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARgamma coactivator-1alpha (PGC-1alpha). NF-kappaB activation in AC16 cardiac cells inhibit ERRalpha and PPARbeta/delta transcriptional activity, resulting in reduced PGC-1alpha and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-kappaB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRalpha and PPARbeta/delta 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-kappaB may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-kappaB 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-kappaB 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-kappaB 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-kappaB acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription. |
