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

doi:10.1016/j.cardiores.2006.12.021

Lack of NF-κB1 (p105/p50) attenuates unloading-induced downregulation of PPARα and PPARα-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

Received July 24, 2006.
Revision received December 19, 2006.
Accepted December 22, 2006.

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.

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