Abstract 140: Effect of Acute β-Adrenergic Receptor Stimulation on Cardiac Function in Gravin Knockout Mice
Gravin, an A kinase anchoring protein expressed in the myocardium, localizes protein kinase A (PKA), protein kinase C and other signaling molecules to the β2-adrenergic receptor (β2-AR). PKA modulates cardiac function by phosphorylating key substrates of the excitation-contraction coupling mechanism such as troponin I, phospholamban, L-type Ca2+ channels and the ryanodine receptor. PKA is activated upon agonist stimulation of β-ARs, thus, the purpose of this study was to determine whether disruption of the PKA/Gravin interaction would alter cardiac function upon β-AR stimulation. WT and gravin-knockout (KO) mice were given an acute challenge with isoproterenol (ISO; 0.25μg/g) injected intraperitoneally, then cardiac function was measured via echocardiography. Control animals were injected with an equal volume of 0.002% ascorbic acid. All experiments were performed with n≥6. Baseline electrocardiography revealed no differences between the WT and KO mice prior to treatment. Additionally, there were no significant differences in body weight or left ventricular (LV) mass between the WT and gravin-KO mice. As expected, heart rate was equally increased in both ISO treated groups when compared to their respective controls (WT vehicle: 489±28.9; KO vehicle: 447.8±20.1; WT ISO: 596.4±8.1; KO ISO: 570.7±16.4; BPM; p<0.0001). However, cardiac output was significantly increased in the gravin-KO vehicle mice as well as in the gravin-KO mice acutely challenged with ISO compared to their WT counterparts (WT vehicle: 19.82±1.18; KO vehicle: 24.78±1.00; WT ISO: 26.97±1.35; KO ISO: 32.84±1.39; ml/min; p<0.0001). Similarly, stroke volume was also much greater in both the vehicle and ISO treated gravin-KO mice than the respective WT group (WT vehicle: 43.94±4.01; KO vehicle: 51.30±2.36; WT ISO: 54.47±4.16; KO ISO: 68.03±2.67; µl; p=0.0056). Finally, LV fractional shortening was also significantly enhanced in both gravin-KO groups when compared with WT mice (WT vehicle: 33.89±2.47; KO vehicle: 43.00±3.25; WT ISO: 54.47±4.16; KO ISO: 68.03±2.67; %; p<0.0001). This data indicates that disruption of gravin’s scaffold mediated signaling is able to increase baseline contractility as well as augment contractility in response to acute β-AR stimulation.
- © 2012 by American Heart Association, Inc.