TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model.
OBJECTIVE
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).


RESULTS
Exposure of AC16 cells to TNF-alpha inhibited the expression of peroxisome proliferator-activated receptor coactivator 1alpha (PGC-1alpha), 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-1alpha expression in the heart compared with that of control mice. The mechanism by which TNF-alpha reduced PGC-1alpha expression in vitro appeared to be largely mediated via both p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways. PGC-1alpha 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 beta/delta and estrogen-related receptor alpha transcription factors.


CONCLUSIONS
These results point to PGC-1alpha downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.
Palomer
Xavier
X
Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, IBUB and CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Alvarez-Guardia
David
D
Rodríguez-Calvo
Ricardo
R
Coll
Teresa
T
Laguna
Juan C
JC
Davidson
Mercy M
MM
Chan
Tung O
TO
Feldman
Arthur M
AM
Vázquez-Carrera
Manuel
M
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D047494:PPAR delta; D048068:PPAR-beta; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose