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Cardiovascular Research Advance Access first published online on November 27, 2008
This version [Corrected Proof] published online on December 15, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn327
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

TNF-{alpha} reduces PGC-1{alpha} expression through NF-{kappa}B and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model

Xavier Palomer1, David Álvarez-Guardia1, Ricardo Rodríguez-Calvo1, Teresa Coll1, Juan C. Laguna1, Mercy M. Davidson2, Tung O. Chan3, Arthur M. Feldman3 and Manuel Vázquez-Carrera1,*

1 Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona) and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Faculty of Pharmacy, University of Barcelona, Building A, 643 Diagonal Ave, E-08028 Barcelona, Spain
2 Department of Neurology, Columbia University, Russ Berrie Medical Pavilion, Room 301, 1150 St Nicholas Avenue, New York, NY 10032, USA
3 Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, RM 813 College Building, 1025 Walnut St., Philadelphia, PA 19107, USA

* Corresponding author. Tel: +34 93 4024531; fax: +34 93 4035982.E-mail address: mvazquezcarrera{at}ub.edu

Aims: Inflammatory responses in the heart that are driven by sustained increases in cytokines have been associated with several pathological processes, including cardiac hypertrophy and heart failure. Emerging data suggest a link between cardiomyopathy and myocardial metabolism dysregulation. To further elucidate the relationship between a pro-inflammatory profile and cardiac metabolism dysregulation, a human cell line of cardiac origin, AC16, was treated with tumour necrosis factor-{alpha} (TNF-{alpha}).

Methods and results: Exposure of AC16 cells to TNF-{alpha} inhibited the expression of peroxisome proliferator-activated receptor coactivator 1{alpha} (PGC-1{alpha}), an upstream regulator of lipid and glucose oxidative metabolism. Studies performed with cardiac-specific transgenic mice (Mus musculus) overexpressing TNF-{alpha}, which have been well characterized as a model of cytokine-induced cardiomyopathy, also displayed reduced PGC-1{alpha} expression in the heart compared with that of control mice. The mechanism by which TNF-{alpha} reduced PGC-1{alpha} expression in vitro appeared to be largely mediated via both p38 mitogen-activated protein kinase and nuclear factor-{kappa}B pathways. PGC-1{alpha} downregulation resulted in an increase in glucose oxidation rate, which involved a reduction in pyruvate dehydrogenase kinase 4 expression and depended on the DNA-binding activity of both peroxisome proliferator-activated receptor β/{delta} and estrogen-related receptor {alpha} transcription factors.

Conclusion: These results point to PGC-1{alpha} downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.

KEYWORDS Peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha}; NF-{kappa}B; TNF-{alpha}

Time for primary review: 39 days


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