Activation of Cardiac Hypertrophic Signaling Pathways in a Transgenic Mouse with the Human Thr400Asn Mutation
Résumé
Human mutations in , 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 (TG), 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 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 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 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 mice were a consequence of increased AMPK activity, we crossbred TG with TG 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 mutation is associated with the early activation of NF-κB and Akt signaling pathway, which mediates cardiac hypertrophy.
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