Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation

Sanjay K Banerjee; Kenneth R McGaffin; Xueyin N Huang; Ferhaan Ahmad

doi:10.1016/j.bbadis.2009.12.001

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Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation

Journal article

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Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation

Sanjay K Banerjee, Kenneth R McGaffin, Xueyin N Huang and Ferhaan Ahmad

Biochimica et biophysica acta. Molecular basis of disease, Vol.1802(2), pp.284-291

2010

DOI: 10.1016/j.bbadis.2009.12.001

PMID: 20005292

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Abstract

Human mutations in PRKAG2, the gene encoding the γ2 subunit of AMP activated protein kinase (AMPK), cause a glycogen storage cardiomyopathy. In a transgenic mouse with cardiac specific expression of the Thr400Asn mutation in PRKAG2 (TG T400N), we previously reported initial cardiac hypertrophy (ages 2–8 weeks) followed by dilation and failure (ages 12–20 weeks). We sought to elucidate the molecular mechanisms of cardiac hypertrophy. TG T400N mice showed significantly increased cardiac mass/body mass ratios up to ∼ 3-fold beginning at age 2 weeks. Cardiac expression of ANP and BNP were ∼ 2- and ∼ 5-fold higher, respectively, in TG T400N relative to wildtype (WT) mice at age 2 weeks. NF-κB activity and nuclear translocation of the p50 subunit were increased ∼ 2- to 3-fold in TG T400N hearts relative to WT during the hypertrophic phase. Phosphorylated Akt and p70S6K were elevated ∼ 2-fold as early as age 2 weeks. To ascertain whether these changes in TG T400N mice were a consequence of increased AMPK activity, we crossbred TG T400N with TG α2DN mice, which express a dominant negative, kinase dead mutant of the AMPK α2 catalytic subunit and have low myocardial AMPK activity. Genetic reversal of AMPK overactivity led to a reduction in hypertrophy, nuclear translocation of NF-κB, phosphorylated Akt, and p70S6K. We conclude that inappropriate activation of AMPK secondary to the T400N PRKAG2 mutation is associated with the early activation of NF-κB and Akt signaling pathway, which mediates cardiac hypertrophy.

Heart

NF-κB

AMPK

AKT

Transgenic Mouse

Hypertrophy

Details

Title: Subtitle: Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation
Creators: Sanjay K Banerjee - Cardiovascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Kenneth R McGaffin - Cardiovascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Xueyin N Huang - Cardiovascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Ferhaan Ahmad - Cardiovascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Resource Type: Journal article
Publication Details: Biochimica et biophysica acta. Molecular basis of disease, Vol.1802(2), pp.284-291
DOI: 10.1016/j.bbadis.2009.12.001
PMID: 20005292
NLM abbreviation: Biochim Biophys Acta Mol Basis Dis
ISSN: 0925-4439
eISSN: 1879-260X
Publisher: Elsevier B.V
Grant note: name: American Heart Association Scientist Development Grant (FA), Postdoctoral Fellowships from the American Heart Association and the Hillgrove Foundation (SKB), and the Cardiovascular Institute of the University of Pittsburgh (Barry London, Director) (FA). FA is a Doris Duke Charitable Foundation Clinical Scientist
Language: English
Date published: 2010
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025570702771

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