Abstract 19097: Mutant Gravin Positively Modulates Cardiac Hypertrophy Following Chronic Beta Adrenergic Stimulation
Gravin, an A kinase anchoring protein (AKAP), scaffolds protein kinase A (PKA) and other signaling molecules to the β2-adrenergic receptor (AR). Gravin plays a vital role in the desensitization of the β2-AR upon agonist stimulation. The objective of this study was to evaluate whether disruption of PKA/gravin interaction prevents cardiac hypertrophy induced by chronic β-AR stimulation and to correlate ventricular hemodynamics to cardiac hypertrophy. Chronic β-AR stimulation was induced in wild-type (WT) and gravin truncated (t/t) mutant mice with isoproterenol (ISO) (60mg/kg/day for 14 days). Ascorbic acid (AA) was used as control. The heart to body weight (HW/BW) ratio, an indicator of hypertrophy, showed that WT-ISO (5.71±0.28) had a significantly higher ratio as compared to WT-AA (3.86±0.082) whereas there was no significant difference between t/t-ISO (4.88±0.24) and t/t-AA (4.31±0.24) groups. Expression of atrial natriuretic factor - a marker of cardaic hypertrophic - was quantified using RT-qPCR and found to be significantly higher in WT-ISO compared to WT-AA but with no significant difference between the t/t-AA and t/t-ISO groups. Next, in vivo performance was evaluated by pressure volume measurements. dP/dt max, indicative of the left ventricular performance was significantly lower in the WT-ISO (7676±376.1) compared to the WT-AA (10175±640.9) with no significant difference between the t/t-ISO (7021±405.5) and t/t-AA (8857±778.2) groups. Ees, representing a parameter of contractility was significantly decreased in the WT-ISO (3.80±0.43) as compared to the WT-AA (7.36 ±0.96) whereas t/t-AA (8.42±1.92) and t/t-ISO (9.77±1.17) groups exhibited no significant differences. Finally the diastolic performance parameter tau was significantly elevated in WT-ISO (9.02±0.19) as compared to the WT-AA (6.76±0.36) whereas t/t-AA (7.28±0.43) and t/t-ISO (7.67±0.54) groups had similar values. Overall, mutant gravin mice (t/t) were resistant to cardiac hypertrophy and had preserved cardiac hemodynamics in response to chronic β-AR stimulation, as compared to WT mice. The data suggests that modulation of gravin and its interaction with the binding partners may play an important role in the progression of heart failure due to cardiac hypertrophy.
- © 2013 by American Heart Association, Inc.