Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation.
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.
Banerjee
Sanjay K
SK
Cardiovascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213-2582, USA.
McGaffin
Kenneth R
KR
Huang
Xueyin N
XN
Ahmad
Ferhaan
F
D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D001216:Asparagine; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology*; D017931:DNA Primers; D052120:Glycogen Storage Disease Type IIb / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D013912:Threonine; D015854:Up-Regulation
D017931:DNA Primers; D016328:NF-kappa B; D013912:Threonine; D012313:RNA; D001216:Asparagine; C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases