Lack of NF-κB1 (p105/p50) attenuates unloading-induced downregulation of PPARα and PPARα-regulated gene expression in rodent heart

Peter Razeghi, Mou Er Wang, Keith A. Youker, Leonard Golfman, Stanislaw Stepkowski, Heinrich Taegtmeyer

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Objective: Unloading of the rodent heart activates the fetal gene program, decreases peroxisome proliferator-activated receptor α (PPARα) and PPARα-regulated gene expression (MCAD), and induces cardiomyocyte atrophy. NF-κB regulates the fetal gene program and PPARα-regulated gene expression during cardiac hypertrophy and induces atrophy in skeletal muscle. Our objective was to test the hypothesis that NF-κB is the regulator for activation of the fetal gene program, for downregulation of PPARα and PPARα-regulated gene expression, and for cardiomyocyte atrophy in the heart subjected to mechanical unloading. Methods: Activation of the inhibitory κ B kinase β (IKKβ)/NF-κB pathways were measured in the heterotopically transplanted rat heart using Western blotting of total and phospho-IKKβ and using transcription factor ELISA's for the five members of the NF-κB family (p65 (Rel A), p105/p50, c-Rel, RelB, and p100/p52). In loss of function experiments, we transplanted hearts of p105/p50 knockout mice into wildtype mice and compared changes in gene expression and cardiomyocyte size with wildtype hearts transplanted into wildtype mice. Results: Total and phospho-IKKβ levels significantly increased in the transplanted heart seven days after surgery. The activation of IKKβ was paralleled by increased DNA binding activity of p65 and p105/p50. Mechanical unloading induced myosin heavy chain β expression and decreased cardiomyocyte size in hearts of both wildtype and p105/p050 knockout animals. In contrast, the downregulation of PPARα and MCAD was significantly attenuated or prevented in the hearts of p105/p50 knockout mice. Conclusions: The IKKβ/p65/p50 pathway is activated in the unloaded rodent heart and a likely regulator for the downregulation of PPARα and PPARα-regulated gene expression.

Original languageEnglish (US)
Pages (from-to)133-139
Number of pages7
JournalCardiovascular Research
Volume74
Issue number1
DOIs
StatePublished - Apr 1 2007

Keywords

  • Atrophy
  • NF-κB
  • PPAR alpha
  • Remodeling
  • Unloading

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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