Lack of NF-kappaB1 (p105/p50) attenuates unloading-induced downregulation of PPARalpha and PPARalpha-regulated gene expression in rodent heart.
OBJECTIVE
Unloading of the rodent heart activates the fetal gene program, decreases peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARalpha-regulated gene expression (MCAD), and induces cardiomyocyte atrophy. NF-kappaB regulates the fetal gene program and PPARalpha-regulated gene expression during cardiac hypertrophy and induces atrophy in skeletal muscle. Our objective was to test the hypothesis that NF-kappaB is the regulator for activation of the fetal gene program, for downregulation of PPARalpha and PPARalpha-regulated gene expression, and for cardiomyocyte atrophy in the heart subjected to mechanical unloading.


METHODS
Activation of the inhibitory kappa B kinase beta (IKKbeta)/NF-kappaB pathways were measured in the heterotopically transplanted rat heart using Western blotting of total and phospho-IKKbeta and using transcription factor ELISA's for the five members of the NF-kappaB 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-IKKbeta levels significantly increased in the transplanted heart seven days after surgery. The activation of IKKbeta 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 PPARalpha and MCAD was significantly attenuated or prevented in the hearts of p105/p50 knockout mice.


CONCLUSIONS
The IKKbeta/p65/p50 pathway is activated in the unloaded rodent heart and a likely regulator for the downregulation of PPARalpha and PPARalpha-regulated gene expression.
Razeghi
Peter
P
Division of Cardiology, University of Texas Houston-Medical School, Houston, Texas 77030, USA.
Wang
Mou-Er
ME
Youker
Keith A
KA
Golfman
Leonard
L
Stepkowski
Stanislaw
S
Taegtmeyer
Heinrich
H
D000818:Animals; D001696:Biomechanical Phenomena; D048429:Cell Size; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D050437:Genes, Developmental; D016027:Heart Transplantation; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D047493:PPAR alpha; D004247:DNA; D051550:I-kappa B Kinase