AMP-Activated Protein Kinase can negatively modulate Ornithine Decarboxylase activity in cardiomyoblasts

The responses of AMP-Activated Protein Kinase (AMPK) and Ornithine decarboxylase (ODC) to isoproterenol have been examined in H9c2 cardiomyoblasts, a cell model of cardiac hypertrophy. AMPK represents the link between cell growth and energy availability whereas ODC, the key enzyme in polyamine biosynthesis, is essential for all growth processes including the development of cardiac hypertrophy. Isoproterenol rapidly induced ODC activity in H9c2 cardiomyoblasts by promoting the synthesis of the enzyme protein. The increase in enzyme activity became significant between 15 and 30 minutes after the treatment. At the same time, isoproterenol stimulated the phosphorylation of AMPKα catalytic subunits (Thr172), which could be observed as soon as 15 minutes. Downregulation of both α1 and α2 isoforms of the AMPK catalytic subunit by siRNA to knockdown AMPK enzymatic activity, led to superinduction of ODC in isoproterenol-treated cardiomyoblasts. Downregulation of AMPKα increased ODC activity even in cells treated with other adrenergic agonists and in untreated cells, but was without effect when ODC was induced by hypoxia, suggesting that ODC modulation by AMPK is not a general event, but is stimulus-dependent. In conclusion, isoproterenol quickly activates in H9c2 cardiomyoblasts two events that seem to contrast one another. The first one, an increase in ODC activity, is linked to cell growth, whereas the second, AMPK activation, is a homeostatic mechanism that negatively modulates the first. The modulation of ODC activity by AMPK can represent a self-regulating mechanism that may contribute to control the development of heart hypertrophy.