Abstract 175: Deletion of AMPK-Alpha2 Intensifies the Insulin-Induced p70S6K Activation in Normoxic Heart and the Isoproterenol-Induced Ventricular Hypertrophy
Background. It has been recently suggested that the AMP-activated protein kinase (AMPK) could play a significant role in the control of protein synthesis during ischemia. It remains uncertain, however, whether AMPK also participates inthe control of protein synthesis under normoxic conditions or during the development of cardiac hypertrophy.
Aim. Accordingly, we sought to evalute the potential contribution of AMPK to the control of protein synthesis in these different conditions by use of AMPKα2 knock-out (α2−/ −) mice.
Methods. The role of AMPK in controlling the protein signaling pathway was tested in isolated perfused mice hearts perfused in the presence or absence of 100 nM insulin and submitted or not to 10 min of no-flow ischemia. The implication of AMPK in the development of cardiac hypertrophy was tested in wild-type and KO mice submitted to daily injections of 50 mg/kg isoproterenol for 7days to induce cardiac hypertrophy (evaluated by serial 2D echocardiograms).
Results. Under normoxic conditions, insulin-induced similar activation of protein kinase B (3.00 ± 0.02 in WT versus 2.80 ± 0.02 mU/mg in α2−/ − mice) and PKB-dependent phosphorylation of mTOR . By contrast, the absence of AMPKα2 caused a significant increase of PKB/mTOR mediated phosphorylation and activition of p70S6 kinase (4.8 ± 0.6 in WT versus 6.8 ± 0.5 mU/mg in α2−/ − mice; p<0.05). This was accompanied by an increase in the insulin-induced phosphorylation of the S6 protein. By contrast, ischemia provoked a similar decrease in insulin-induced PKB/mTOR/ p70S6K stimulation in both WT and α2 −/ − mice. To determine whether the increase in mTOR/p70S6K pathway seen in α2−/ − under normoxic conditions influences the development of cardiac hypertrophy, WT and α2−/ − mice were submitted to daily injections of isoproterenol. The anterior wall thickness, measured by echo, increased more in α2−/ − than in WT mice (+24.0% vs 9.4% in WT, p<0.01). Similarly, echo-derived left ventricular (LV) mass increased more in α2−/ − than in WT mice (+73% vs. +42%, p<0.01).
Conclusions: Our results show that the AMPKα2 isoform plays a role in the regulation of p70S6K activity under normoxic but not under ischemic conditions. Moreover, the absence of this isoform amplifies the isoproterenol-induced LV hypertrophy.