Abstract 17932: Increased Cardiac Contractility and Improved Cardiac Remodeling in Gravin (AKAP12) Knock-out Mice in Response to Chronic β-Adrenergic Receptor Stimulation
Beta-adrenergic receptor (β-AR) stimulation is the primary mechanism to increase cardiac contractility. However, chronic β-AR stimulation, as occurs in heart failure, results in receptor desensitization and reduced contractility. β-AR stimulation signals through PKA-dependent phosphorylation, in part by PKA binding to A-Kinase Anchoring Proteins (AKAPs) to influence Ca2+ homeostasis and thus contractility. Gravin (AKAP12), an AKAP, functions to localize PKA, PP2B and PKC to the β2-AR and is believed to be involved in receptor desensitization. We now report, the generation of gravin knock-out (gravin-KO) mice using gene trap technology (ES cells from BayGenomics). Absence of the gravin gene and protein were confirmed by qRT-PCR and Western blot, respectively. We tested whether chronic isoproterenol (ISO; 30 mg/kg/day × 14 days) stimulation affected contractility and remodeling in gravin-KO mice by echocardiography. Left ventricular (LV) fractional shortening, a cardiac contractility parameter, was significantly increased in gravin-KO mice [55.91±5.98 (gravin-KO) vs 35.33±3.72 (WT); p<0.05]. Similarly, significant increases were observed in the ejection fraction, stroke volume and cardiac output. Conversely, the LV mass to body weight ratio, a cardiac remodeling parameter, was significantly decreased in gravin-KO mice [3.41±0.20 (gravin-KO) vs 4.32±0.21 (WT); p<0.05]. A significant decrease was also observed in the diastolic LV posterior wall thickness. ECG analysis showed significant decreases in the heart rate variability and the coefficient of variance of the RR interval in gravin-KO mice. Additionally, we observed increased cell shortening and decreased [Ca2+]i transients in fura-2 loaded gravin-KO myocytes in the presence of 1 μM ISO. This increased cardiac function in gravin-KO mice, in response to chronic β-AR stimulation, was associated with decreased CaMKII and Akt phosphorylation. Together, increased contractility and decreased arrhythmias in gravin-KO mice, following chronic β-AR stimulation, improved cardiac remodeling via enhanced [Ca2+]i homeostasis. This may represent a novel mechanism whereby disrupting gravin's role as a multi-component regulator of PKA signaling can increase cardiac contractility.
- © 2010 by American Heart Association, Inc.