Abstract 17633: Beta-3 Adrenergic Receptor Deficiency Reverses the Cardioprotective Effects of Exercise by Attenuating AMPK Phosphorylation and eNOS Coupling
Background: Exercise training confers sustainable protection against ischemia-reperfusion injury. However, the mechanism by which this process occurs is not fully understood. Previously, we reported that voluntary exercise (VE) reduced myocardial ischemia-reperfusion injury by increasing the activation of endothelial Nitric Oxide Synthase (eNOS) and increasing nitric oxide (NO) levels. Additionally, we found that β3-adrenergic receptors (β3-ARs) play a critical role in regulating the activation of eNOS and the generation of NO in response to exercise and play a critical role in exercise-mediated cardioprotection. Here we tested the hypothesis that AMP-activated protein kinase (AMPK) links β3-ARs to eNOS during exercise.
Methods and Results: Wild-type (WT) mice that engaged in VE for 4 weeks revealed a 22% reduction in infarct size per area-at-risk (INF/AAR) following 45 min of myocardial ischemia and 24 hour of reperfusion when compared to sedentary (SED) mice. In contrast, β3-AR deficient mice (β3-AR KO) displayed a 41% increase in infarct size compared to β3-AR KO SED mice. In separate experiments, SED and VE mice from both strains were sacrificed immediately after the training period and heart tissue was excised and processed for Western blot analysis. In WT mice, VE increased the phosphorylation of AMPK and induced eNOS coupling (evaluated with monomer/dimer blots). In contrast, VE failed to increase AMPK phosphorylation in β3-AR KO mice. Additional studies revealed that VE rendered eNOS less coupled and increased NOS-dependent superoxide levels in β3-AR KO mice.
Conclusion: These findings provide important information that VE provides cardioprotection by activating and coupling eNOS via the stimulation of a β3-AR-AMPK signaling pathway.
- © 2013 by American Heart Association, Inc.