Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 27, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn327
TNF-
reduces PGC-1 expression through NF-
B and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model
1 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 Ave. 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: Dr. Manuel Vázquez Carrera, Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona. Building A, 643 Diagonal Ave., E-08028, Barcelona. Spain. E-mail: mvazquezcarrera{at}ub.edu, Phone: 34 93 4024531; Fax: 34 93 4035982
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 proinflammatory profile and cardiac metabolism dysregulation, a human cell line of cardiac origin, AC16, was treated with tumor necrosis factor-
(TNF-).
Methods and Results: Exposure of AC16 cells to TNF- inhibited expression of peroxisome proliferator-activated receptor coactivator 1 (PGC-1), an upstream regulator of lipid and glucose oxidative metabolism. Studies performed with cardiac-specific transgenic mice (Mus musculus) overexpressing TNF-, which have been well characterized as a model of cytokine-induced cardiomyopathy, also displayed reduced PGC-1 expression in the heart compared to that of control mice. The mechanism by which TNF- reduced PGC-1 expression in vitro appeared to be largely mediated via both p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-
B (NF-B) pathways. PGC-1 downregulation resulted in an increase in glucose oxidation rate, which involved a reduction in pyruvate dehydrogenase kinase 4 (PDK4) expression and depended on the DNA binding activity of both peroxisome proliferator-activated receptor (PPAR)β/
and estrogen-related receptor (ERR) transcription factors.
Conclusion: These results point to PGC-1 downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.
Time for primary review: 39 Days
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