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

Abstract

Human mutations in PRKAG2, the gene encoding the gamma2 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 approximately 3-fold beginning at age 2 weeks. Cardiac expression of ANP and BNP were approximately 2- and approximately 5-fold higher, respectively, in TG(T400N) relative to wildtype (WT) mice at age 2 weeks. NF-kappaB activity and nuclear translocation of the p50 subunit were increased approximately 2- to 3-fold in TG(T400N) hearts relative to WT during the hypertrophic phase. Phosphorylated Akt and p70S6K were elevated approximately 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(alpha2DN) mice, which express a dominant negative, kinase dead mutant of the AMPK alpha2 catalytic subunit and have low myocardial AMPK activity. Genetic reversal of AMPK overactivity led to a reduction in hypertrophy, nuclear translocation of NF-kappaB, 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-kappaB and Akt signaling pathway, which mediates cardiac hypertrophy.

• Authors: Sanjay K Banerjee, Kenneth R McGaffin, Xueyin N Huang, Ferhaan Ahmad
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1802 Issue 2 Pg. 284-91 (Feb 2010) ISSN: 0006-3002 [Print] Netherlands
• PMID: 20005292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Elsevier B.V. All rights reserved.

Chemical References

• DNA Primers
• NF-kappa B
• Threonine
• RNA
• Asparagine
• PRKAG2 protein, human
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (chemistry, genetics, metabolism)
• Amino Acid Substitution
• Animals
• Asparagine
• Cardiomegaly (enzymology, genetics, physiopathology)
• DNA Primers
• Glycogen Storage Disease Type IIb (enzymology, genetics, physiopathology)
• Heart (physiology, physiopathology)
• Humans
• Mice
• Mice, Transgenic
• NF-kappa B (metabolism)
• Phosphorylation
• Polymerase Chain Reaction (methods)
• RNA (genetics, isolation & purification)
• Threonine
• Up-Regulation