Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2007 Apr 1;74(1):133-9.
doi: 10.1016/j.cardiores.2006.12.021. Epub 2007 Jan 3.

Lack of NF-kappaB1 (p105/p50) attenuates unloading-induced downregulation of PPARalpha and PPARalpha-regulated gene expression in rodent heart

Peter Razeghi  1 , Mou-Er Wang, Keith A Youker, Leonard Golfman, Stanislaw Stepkowski, Heinrich Taegtmeyer
Affiliations
Comparative Study

Lack of NF-kappaB1 (p105/p50) attenuates unloading-induced downregulation of PPARalpha and PPARalpha-regulated gene expression in rodent heart

Peter Razeghi et al. Cardiovasc Res. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Seven days of mechanical unloading significantly increase protein levels of total and phospho-IKKβ levels in the rat heart (n=7, * p < 0.05). Fig. 1a shows representative western blots and Fig. 1b shows densitometry of total and phospho-IKKβ protein expression normalized to beta-tubulin in the control and unloaded heart.
Figure 2.
Figure 2.
DNA binding activities of p65 (a) and p50 (b), but not c-Rel (c), Rel-B (d), or p52 (e) significantly increase in the unloaded rat heart seven days after surgery (n=7, * p < 0.05).
Figure 3.
Figure 3.
Mechanical unloading of the mouse heart significanetly increases MHCβ, and decreases PPARα in hearts of wildtype and p50−/− mice (a, b, n=5, * p < 0.05, ** p < 0.01, *** p < 0.001). MCAD gene expression only significantly decreased in unloaded wildtype hearts (n=5, ** p < 0.01), but only showed a trend to decrease in unloaded p50−/− hearts (c, p = 0.10). Transcript levels of PPARα and MCAD were significantly higher in unloaded hearts of p50−/− mice than in unloaded hearts of mice (b, c, n=5, # p < 0.05, ## p < 0.01). PDK4 and UCP3 gene expression significantly decreased in unloaded hearts and increased in unloaded p50−/− hearts (d, e, n=5, * p < 0.05, ** p < 0.01). Transcript levels of PDK4 and UCP3 were significantly higher in unloaded hearts of p50−/− mice than in unloaded hearts of mice (d, e, n=5, ## p < 0.01, ### p < 0.001).
Figure 4.
Figure 4.
Hematoxylin-eosin staining of native (a and c), unloaded wildtype hearts (b), and unloaded hearts of p50−/− mice (d). Cardiomyocyte size significantly decreased in unloaded wildtype and unloaded p50−/− hearts (e, n=5, ** p < 0.01) and did not significantly differ between the two groups.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Depre C, Shipley GL, Chen W, Han Q, Doenst T, Moore ML, et al. Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat Med. 1998;4:1269–1275. - PubMed
    1. Sharma S, Ying J, Razeghi P, Stepkowski S, Taegtmeyer H. Atrophic remodeling of the transplanted rat heart. Cardiology. 2006;105:128–136. - PubMed
    1. Razeghi P, Sharma S, Ying J, Li YP, Stepkowski S, Reid MB, et al. Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation. Circulation. 2003;108:2536–2541. - PubMed
    1. Thanos D, Maniatis T. Nf-κb: A lesson in family values. Cell. 1995;80:529–532. - PubMed
    1. Freund C, Schmidt-Ullrich R, Baurand A, Dunger S, Schneider W, Loser P, et al. Requirement of nuclear factor-κb in angiotensin ii- and isoproterenol-induced cardiac hypertrophy in vivo. Circulation. 2005;111:2319–2325. - PubMed

Publication types

MeSH terms