Abstract 1508: Role Of β-adrenergic Signaling In Cardiac-Specific ErbB-1 Mutant-Induced Cardiac Dysfunction
Background: The ErbB-1/EGFR tyrosine kinase receptor is essential for mammalian cardiac development and function. Using cardiac-specific and time-controlled gene expression system, we showed that ErbB-1 mutant mice display cardiac dilation, cardiac dysfunction, and increased mortality. However, the mechanism of ErbB-1-mediated control of cardiac function is not clear. ErbB-1 transactivation by G-protein coupled receptors is known to be an important process and, as G-protein coupled β-adrenergic signaling is a key mediator of myocardial contractility, we examined the hypothesis that β-adrenergic signaling is impaired in ErbB-1 mutants.
Methods: We performed high frequency echocardiography in young adult mice under isoflurane anesthesia. ErbB-1 mutants induced with Ponasterone A (Mut + PonA) were compared with appropriate controls. Resting cardiac function (n = 4 – 6) was studied following early (1.5 mo) and long-term (5 mo) PonA induction. We then injected the β1-adrenergic receptor agonist, dobutamine (DOBU; 1mg/kg IP; n = 3–4) and the adenylyl cyclase activator Forskolin analogue, NKH 477 (FSK; 0.5mg/kg IP; n = 4) in separate groups of mutants and controls (PonA induction - at least 1.5 mo).
Results: There were significant decreases in resting ejection fraction (EF) and fractional shortening (FS) and increases in left ventricular internal diameter in systole (LVIDs) and LV volume in systole (LVVols) following both early and long-term induction in ErbB-1 mutants compared to controls. Following DOBU injections, the increases in resting EF and FS and, decreases in resting LVIDs and LVVols with respect to baseline were significantly diminished in ErbB-1 mutants. Following FSK injections, the inotropic effects were similar in all groups.
Conclusion: These results indicate diminished LV contractile reserve in cardiac-specific ErbB-1 mutants in response to β1-adrenergic stimulation that can be rescued by activation of the adenylyl cyclase system in vivo.