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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1802

Article

Banerjee, Sanjay K.¹  McGaffin, Kenneth R.¹  Huang, Xueyin N.¹  Ahmad, Ferhaan^1,2 

[1] Univ Pittsburgh, Cardiovasc Inst, Dept Med, Pittsburgh, PA 15213 USA

[2] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15213 USA

关键词: AMPK;    Hypertrophy;    AKT;    NF-kappa B;    Transgenic Mouse;    Heart;   

DOI  :  10.1016/j.bbadis.2009.12.001

来源: Elsevier

【 摘 要 】

Human mutations in PRKAG2, the gene encoding the gamma 2 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 28 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 similar to 3-fold beginning at age 2 weeks. Cardiac expression of ANP and BNP were similar to 2- and similar to 5-fold higher, respectively, in TG(T400N) relative to wildtype (WT) mice at age 2 weeks. NF-kappa B activity and nuclear translocation of the p50 subunit were increased similar to 2- to 3-fold in TG(T400N) hearts relative to WT during the hypertrophic phase. Phosphorylated Akt and p70S6K were elevated similar to 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(alpha 2DN) mice, which express a dominant negative, kinase dead mutant of the AMPK alpha 2 catalytic subunit and have low myocardial AMPK activity. Genetic reversal of AMPK overactivity led to a reduction in hypertrophy, nuclear translocation of NF-kappa B, 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-kappa B and Akt signaling pathway, which mediates cardiac hypertrophy. (C) 2009 Elsevier B.V. All rights reserved.

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