A distinct AMP-activated protein kinase phosphorylation site characterizes cardiac hypertrophy induced by L-thyroxine and angiotensin II.

1. The purpose of the present study was to evaluate differences in the AMP-activated protein kinase (AMPK) phosphorylation sites in cardiac hypertrophy induced by L-thyroxine and angiotensin (Ang) II. 2. Cardiac hypertrophy was induced in wild-type and AMPKalpha2-knockout mice by treatment with 1 mg/kg, i.p., thyroxine or 1.44 mg/kg per day AngII for 14 days. The phenotype of the hypertrophy was evaluated using echocardiographic measurements and histological analyses. The phosphorylation of AMPK at alpha-Ser(485/491) and alpha-Thr(172) was determined by western blot analysis. 3. In wild-type mice, the phosphorylation of AMPKalpha-Ser(485/491) was significantly elevated in the AngII-treated group, but not in the thyroxine-treated group, compared with the vehicle control group. In contrast, the phosphorylation of AMPKalpha-Thr(172) was significantly increased by thyroxine, but not AngII, treatment compared with the vehicle control group. Furthermore, knockout of the AMPKalpha2 subunit abolished phosphorylation at the alpha-Ser(485/491) site and significantly suppressed phosphorylation at the alpha-Thr(172) site, resulting in alleviation of thyroxine- but not AngII-induced hypertrophy. 4. In conclusion, L-thyroxine and AngII induce the phosphorylation of distinct sites of AMPK in cardiac hypertrophy. Phosphorylation of AMPK alpha-Thr(172) may contribute to thyroxine-induced cardiac hypertrophy.