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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-?B (NF-?B) 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-? (ERR?) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPAR? coactivator-1? (PGC-1?). NF-?B activation in AC16 cardiac cells inhibit ERR? and PPAR?/? transcriptional activity, resulting in reduced PGC-1? and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-?B inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERR? and PPAR?/? 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-?B may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-?B 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-?B 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-?B 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-?B acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription.

SUBMITTER: Palomer X 

PROVIDER: S-EPMC3100304 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Palomer Xavier X   Álvarez-Guardia David D   Davidson Mercy M MM   Chan Tung O TO   Feldman Arthur M AM   Vázquez-Carrera Manuel M  

PloS one 20110523 5


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 tra  ...[more]

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