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TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a

Xavier Palomer1, David Alvarez-Guardia, Ricardo Rodríguez-Calvo

  • 1Pharmacology 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.

Cardiovascular Research
|November 29, 2008
PubMed

Insights

Tumor necrosis factor-alpha (TNF-alpha) reduces cardiac peroxisome proliferator-activated receptor coactivator 1alpha (PGC-1alpha) expression, impacting myocardial metabolism. This downregulation may contribute to heart failure in inflammatory metabolic conditions.

Area of Science:

  • Cardiovascular Biology
  • Molecular Metabolism
  • Inflammation Research

Background:

  • Cytokine-driven inflammation is linked to cardiac hypertrophy and heart failure.
  • Myocardial metabolism dysregulation is increasingly associated with cardiomyopathy.
  • Tumor necrosis factor-alpha (TNF-alpha) is a key pro-inflammatory cytokine implicated in cardiac pathology.

Purpose of the Study:

  • To investigate the relationship between pro-inflammatory signaling and cardiac metabolic dysfunction.
  • To determine the effect of TNF-alpha on key metabolic regulators in cardiac cells.
  • To elucidate the molecular mechanisms linking inflammation to altered cardiac metabolism.

Main Methods:

  • Treatment of human cardiac AC16 cells with TNF-alpha.
  • Analysis of peroxisome proliferator-activated receptor coactivator 1alpha (PGC-1alpha) expression.
  • Studies in cardiac-specific transgenic mice overexpressing TNF-alpha.
  • Investigation of signaling pathways including p38 MAPK and NF-kappaB.
  • Assessment of glucose oxidation rates and key metabolic gene expression.

Main Results:

  • TNF-alpha inhibited PGC-1alpha expression in AC16 cells and in the hearts of TNF-alpha transgenic mice.
  • The inhibitory effect of TNF-alpha on PGC-1alpha was mediated by p38 MAPK and NF-kappaB pathways.
  • PGC-1alpha downregulation led to increased glucose oxidation via reduced pyruvate dehydrogenase kinase 4 expression.
  • This metabolic shift was dependent on PPAR beta/delta and ERR alpha transcription factors.

Conclusions:

  • Downregulation of PGC-1alpha by TNF-alpha is a significant finding in cardiac inflammation.
  • This mechanism may contribute to cardiac dysfunction and heart failure in inflammatory metabolic disorders.
  • Targeting PGC-1alpha or related pathways could offer therapeutic strategies for inflammatory cardiomyopathy.
Abstract

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