Description:
<jats:p>
The steroid hormone 17β-estradiol (E2) regulates several biological processes. In contrast to its anti-hypertrophic effects under pressure overload, we recently found that E2 induced physiological hypertrophic growth in healthy C57Bl/6J mice but not C57Bl/6N mice. Here, we aimed at the characterization of the effects of E2 in C57Bl/6N mice and tested the hypothesis that β-catenin mediates these E2 effects. Following ovariectomy, 2-month-old C57Bl/6N wild-type and cardiac-specific β-catenin-deleted (β-cat
<jats:sup>Δex2-6</jats:sup>
) mice were randomized to an E2-containing or soy-free (control, CON) diet (
<jats:italic>n</jats:italic>
= 7-13/group). Cardiac function was examined by echocardiography following established procedures. The 3-month physiological dose of E2 led to a higher relative uterus weight compared with CON (
<jats:italic>P</jats:italic>
< 0.001) in both WT and β-cat
<jats:sup>Δex2-6</jats:sup>
mice. The relative heart weight was significantly reduced by E2 compared with CON in WT mice (
<jats:italic>P</jats:italic>
< 0.001), while there was no significant effect in β-cat
<jats:sup>Δex2-6</jats:sup>
mice. Cardiomyocyte cross-sectional area was also significantly decreased by E2 (
<jats:italic>n</jats:italic>
= 5-7/group;
<jats:italic>P</jats:italic>
< 0.001) compared with CON in WT mice, while there was no significant effect in β-cat
<jats:sup>Δex2-6</jats:sup>
mice. Echocardiography revealed a significant decrease in septum width (
<jats:italic>P</jats:italic>
< 0.001) and posterior wall thickness (
<jats:italic>P</jats:italic>
< 0.01) in E2 treated WT mice compared with CON, while there was no significant effect in β-cat
<jats:sup>Δex2-6</jats:sup>
mice (
<jats:italic>n</jats:italic>
= 8/group). These E2-induced structural changes in WT mice were accompanied by a significant decrease in cardiac function, namely a 23% decrease in fractional shortening compared with CON (
<jats:italic>P</jats:italic>
< 0.05), while there was no significant effect in β-cat
<jats:sup>Δex2-6</jats:sup>
mice. Immunoblotting revealed a significant increase in the levels of the ubiquitin ligase and key regulator of proteasome-dependent protein degradation muscle-specific RING finger protein 1 (MuRF1) by E2 compared with CON in WT mice (
<jats:italic>P</jats:italic>
< 0.05), while there was no significant effect in β-cat
<jats:sup>Δex2-6</jats:sup>
mice. Although we hypothesized increased autophagic activity, we found no effect on the autophagy-related protein LC3 in WT or β-cat
<jats:sup>Δex2-6</jats:sup>
mice. In conclusion, our surprising findings show that E2 leads to cardiac atrophy and dysfunction in C57Bl/6N mice via a β-catenin mechanism seemingly in an autophagy-independent manner.
</jats:p>