Abstract 055: β-Catenin Mediates an Interplay between Genetic Background and Growth-Regulating Effects of Estrogen in the Healthy Heart
In diseased hearts, estrogen (E2) has been shown to exert anti-hypertrophic actions. Little is known about the role of E2 in the healthy heart. Our initial aim was to characterize structurally and molecularly the effects of E2 in the healthy mouse heart. Two-month-old female C57Bl/6J mice were ovariectomized and randomized to an E2-containing or soy-free (control, CON) diet (n = 17-18/group). The three-month physiological dose of E2 led to a higher relative heart weight compared with CON (P < 0.001). We also confirmed increased cardiomyocyte cross-sectional area by E2 (P < 0.01). No activation of the fetal gene program and no fibrosis were observed. Transcriptome analysis revealed induction of growth-related pathways by E2, such as the Wnt signaling pathway (n = 5/group; adjusted P < 0.05). To further confirm activation of Wnt/β-catenin signaling, we verified increased nuclear β-catenin protein levels by E2 compared with CON (P < 0.01) and hypothesized that β-catenin mediates the actions of E2. Cardiac deletion of β-catenin blunted the E2 effects on cardiac growth (n = 13/group). Surprisingly, in wild-type littermates with the background C57Bl/6N, E2 decreased the relative heart weight and cardiomyocyte cross-sectional area compared with CON (n = 7-11/group; P < 0.001). This was underlain by decreased nuclear β-catenin protein levels by E2 compared with CON (P < 0.001). Furthermore, E2 increased glycogen synthase kinase 3β (GSK3β) phosphorylation and the endosomal/autophagosomal markers Rab5, Rab7 and LC3-II in C57Bl/6J but not C57Bl/6N mice. Assessing a polymorphism linked to Snap29, we confirmed higher Snap29 protein levels in C57Bl/6J than C57Bl/6N mice (P < 0.01). This could lead to distinct regulation of endosomes and could be the potential cause of the strain difference. In conclusion, E2 regulates cardiac growth through β-catenin in a strain-specific manner. Collectively, we identified a molecular mechanism that demonstrates a divergent response of mouse sub-strains to E2.
- © 2013 by American Heart Association, Inc.