Abstract P112: Estradiol Induces Physiological Hypertrophic Growth in the Healthy Mouse Heart
Estradiol-17beta (E2) has been shown to exert anti-hypertrophic actions by either attenuating or blunting the development of left ventricular hypertrophy. However, the vast majority of these studies have been performed in stressed or diseased hearts. Consequently, very little is known about the actions of E2 in the stress- and disease-free heart. The aim of our study was to identify and characterize structurally and molecularly the role of E2 in the healthy heart. Female C57Bl/6J mice were ovariectomized at the age of two months. Mice were randomly assigned into groups feeding on either an E2-containing (n = 19) or soy-free (Ctrl; n = 19) diet for three months. Following this, all mice were sacrificed and hearts were collected for weight measurement. Left ventricles were analyzed structurally by immunohistochemistry and molecularly by genome-wide expression profiling. E2 led to an increase in the heart weight (11%; P < 0.001) and the heart-to-body weight ratio (32%; P < 0.001) compared to Ctrl mice. Cardiomyocyte cross-sectional area revealed cardiomyocyte hypertrophy in E2 (n = 6) compared to Ctrl (n = 5) mice (32%; P = 0.004). Analysis of the left ventricular transcriptome identified 1059 probe sets (adjusted P ≤ 0.05) differentially expressed between E2 (n = 5) and Ctrl (n = 5). Hypergeometric testing for Gene Ontology showed most genes to be associated with cell cycle, regulation of growth, cell and tissue development. Pathway analysis revealed 140 pathways (adjusted P = 0.05) modulated between the two groups, such as the DNA replication and Wnt signaling pathways. Next, we tested the hypothesis that this hypertrophic effect of E2 is of the physiological type. To this extent, we identified that angiogenesis was increased with cardiac growth as determined by the microarray analysis and VEGF-A protein levels assessed by Western blotting. Furthermore, the embryonic gene program was not activated and no fibrosis was observed in the E2-treated group. In conclusion, our study is the first to demonstrate pro-hypertrophic actions of E2 in the healthy heart through the modulation of growth-related genes and pathways. Due to that we have characterized the hypertrophic effect of E2 as physiological, we expect this effect to be beneficial for the heart.
- © 2011 by American Heart Association, Inc.