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

Objective: Unloading of the rodent heart activates the fetal gene program, decreases peroxisome proliferator-activated receptor alpha (PPAR alpha) and PPAR alpha-regulated gene expression (MCAD), and induces cardiomyocyte atrophy. NF-kappa B regulates the fetal gene program and PPAR alpha-regulated gene expression during cardiac hypertrophy and induces atrophy in skeletal muscle. Our objective was to test the hypothesis that NF-kappa B is the regulator for activation of the fetal gene program, for downregulation of PPAR alpha and PPAR alpha-regulated gene expression, and for cardiomyocyte atrophy in the heart subjected to mechanical unloading. Methods: Activation of the inhibitory kappa B kinase beta (IKK beta)/NF-kappa B pathways were measured in the heterotopically transplanted rat heart using Western blotting of total and phospho-IKK beta and using transcription factor ELISA's for the five members of the NF-kappa B 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-IKK beta levels significantly increased in the transplanted heart seven days after surgery. The activation of IKK beta was paralleled by increased DNA binding activity of p65 and p105/p50. Mechanical unloading induced myosin heavy chain beta expression and decreased cardiomyocyte size in hearts of both wildtype and p105/p050 knockout animals. In contrast, the downregulation of PPAR alpha and MCAD was significantly attenuated or prevented in the hearts of p105/p50 knockout mice. Conclusions: The IKK beta/p65/p50 pathway is activated in the unloaded rodent heart and a likely regulator for the downregulation of PPAR alpha and PPAR alpha-regulated gene expression. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.