Abstract 16969: Improved Cardiac Function in Gravin Knockout Mice Following Acute Beta-Adrenergic Stimulation
Gravin is an A kinase anchoring protein that facilitates the action of protein kinase A (PKA) by targeting the kinase as well as other signaling molecules to the β2-adrenergic receptor (β2-AR). PKA modulates cardiac function by phosphorylating troponin I, phospholamban and other key components of the excitation-contraction coupling mechanism. Disruption of PKA/AKAP interactions has been previously shown to augment cardiac contractility. Therefore, since PKA is primarily activated upon agonist stimulation of β-ARs, the purpose of this study was to determine whether disruption of the PKA/Gravin interaction was sufficient to enhance cardiac function upon β-AR stimulation. To this end, WT and gravin-knockout (KO) mice were acutely challenged by infusion of isoproterenol (ISO; 20pg/g/min) followed by pressure volume relationship analysis. Control animals were injected with an equal volume of vehicle (0.002% ascorbic acid). Heart weight to body weight ratios as well as left ventricular mass to body weight ratios were similar between WT and gravin-KO mice. KO mice had significantly decreased heart rate at baseline that translated into significantly decreased ejection fraction and cardiac output when compared to the WT mice. After ISO stimulation, heart rate was similar among the two genotypes (WT ISO: 561.0 ± 11.2; KO ISO: 549.9 ± 6.8). Additionally, the KO mice hearts responded comparably to WT hearts after ISO stimulation in most parameters despite having a lower baseline. The systolic contractility parameter, dP/dt Max, was significantly increased in KO ISO hearts compared to both its baseline and WT ISO hearts (KO baseline: 7554±588.9, KO ISO; 13132±587.9, WT ISO;10661±285.4, mm Hg, p=0.005). Stroke volume in the KO hearts increased by 43.7% after ISO stimulation versus 14.6% in WT hearts (p=0.001). Similarly, ejection fraction was increased in the KO ISO hearts by 43% compared to 33% in WT ISO hearts (p=0.02). Although PKA activity and phosphorylation of phospholamban and troponin I was significantly increased in both ISO treated groups, there was no difference between WT ISO and KO ISO. This data indicates that disruption of the gravin/PKA scaffolding complex is sufficient to cause an increase in contractility in response to acute β-AR stimulation.
- © 2012 by American Heart Association, Inc.