Copyright © 2007, European Society of Cardiology
Lack of NF-
B1 (p105/p50) attenuates unloading-induced downregulation of PPAR
and PPAR-regulated gene expression in rodent heart
aDivision of Cardiology, University of Texas Houston-Medical School, Houston, Texas, USA
bDivision of Organ Transplantation, University of Texas Houston-Medical School, Houston, Texas, USA
cDepartment of Surgery, Baylor College of Medicine, Houston, Texas, USA
dDepartment of Cardiothoracic and Vascular Surgery, University of Texas Houston-Medical School, Houston, Texas, USA
* Corresponding author. Department of Internal Medicine, Division of Cardiology, University of Texas Houston-Medical School, 6431 Fannin, MSB 1.222, Houston, TX 77030, USA. Tel.: +1 713 500 6569; fax: +1 713 500 0637. Email address: heinrich.taegtmeyer{at}uth.tmc.edu
Objective: Unloading of the rodent heart activates the fetal gene program, decreases peroxisome proliferator-activated receptor 
(PPAR) and PPAR-regulated gene expression (MCAD), and induces cardiomyocyte atrophy. NF-
B regulates the fetal gene program and PPAR-regulated gene expression during cardiac hypertrophy and induces atrophy in skeletal muscle. Our objective was to test the hypothesis that NF-B is the regulator for activation of the fetal gene program, for downregulation of PPAR and PPAR-regulated gene expression, and for cardiomyocyte atrophy in the heart subjected to mechanical unloading.
Methods: Activation of the inhibitory B kinase β (IKKβ)/NF-B 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-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-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 PPAR 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 PPAR and PPAR-regulated gene expression.
KEYWORDS Atrophy; Remodeling; PPAR alpha; NF-B; Unloading