Abstract 346: A Novel Interaction Between E2F and β-adrenergic Pathways Regulates Survival and Growth in Murine Myocardium
The E2F/Pocket protein (Rb) pathway regulates cell growth, differentiation, and death by modulating gene expression. We previously examined this pathway in myocardium via manipulation of E2F6, which represses gene activity independently of Rb. Mice with cardiac specific expression of E2F6 develop dilated cardiomyopathy (DCM) without any signs of hypertrophic growth. We assessed the mechanisms of the apparent failure of compensatory growth as well as their response to the β-adrenergic agonist isoproterenol (iso). E2F6 transgenic (Tg) mice present with left ventricle dilation and significantly reduced ejection fraction as early as 2 weeks which persists into adulthood, but with no apparent increase in left ventricle weight: body weight (LVW:BW). E2F6-Tg mice treated with iso show double the increase in LVW: BW than their Wt counterparts (32% vs 16%, p-value: 0.007). Western blot revealed a specific activation of the β2-adrenergic pathway in Tg myocardium under basal conditions including a ~2-fold increase in β2-adrenergic receptors (β2-AR) (p-value: 8.9E-05), protein kinase A catalytic subunit (PKA-C) (p-value: 0.0176), activated c-SRC tyrosine-protein kinase (p-value: 0.0002), and an induction of the anti-apoptotic gene Bcl2. In contrast, a ~70% decrease in the cardiac growth regulator: AKT1 (p-value 0.0001) and a 4-fold increase in cyclic AMP dependent phosphodiesterase 4D (PDE4D), the negative regulator of PKA activity, was evident in Tg myocardium. The expression of E2F3 was de-regulated by E2F6, but was restored by iso while Rb expression was down-regulated. Thus deregulation of E2F/Rb pathway by E2F6 altered the β-adrenergic signaling pathway such that survival signaling was activated while hypertrophy was repressed resulting in the development of DCM without any increase in muscle mass. These data reveal a novel interplay between E2F and the β adrenergic pathway which regulate cardiac growth and fate.
Author Disclosures: J.L. Major: None. M. Salih: None. B.S. Tuana: None.
- © 2015 by American Heart Association, Inc.