Estrogen Receptor-β Signals Left Ventricular Hypertrophy Sex Differences in Normotensive Deoxycorticosterone Acetate-Salt Mice
We found earlier that deoxycorticosterone acetate-salt treatment causes blood pressure–independent left ventricular hypertrophy, but only in male mice. To test the hypothesis that the estrogen receptor-β (ERβ) protects the females from left ventricular hypertrophy, we treated male and female ERβ-deficient (ERβ−/−) mice and their male and female littermates (wild-type [WT]) with deoxycorticosterone acetate-salt and made them telemetrically normotensive with hydralazine. WT males had increased (+16%) heart weight/tibia length ratios compared with WT females (+7%) at 6 weeks. In ERβ−/− mice, this situation was reversed. Female WT mice had the greatest heart weight/tibia length ratio increases of all of the groups (+23%), even greater than ERβ−/− males (+10%). Echocardiography revealed concentric left ventricular hypertrophy in male WT mice, whereas ERβ−/− females developed dilative left ventricular hypertrophy. The hypertrophic response in female ERβ−/− mice was accompanied by the highest degree of collagen deposition, indicating maladaptive remodeling. ERβ+/+ females showed robust protective p38 and extracellular signal–regulated kinase 1/2 signaling relationships compared with other groups. Calcineurin Aβ expression and its positive regulator myocyte-enriched calcineurin-interacting protein 1 were increased in deoxycorticosterone acetate-salt female ERβ−/− mice, yet lower than in WT males. Endothelin increased murine cardiomyocyte hypertrophy in vitro, which could be blocked by estradiol and an ERβ agonist. We conclude that a functional ERβ is essential for inducing adaptive p38 and extracellular signal–regulated kinase signaling, while reducing maladaptive calcineurin signaling in normotensive deoxycorticosterone acetate female mice. Our findings address the possibility of sex-specific cardiovascular therapies.
- Received November 1, 2010.
- Revision received December 1, 2010.
- Accepted January 12, 2011.
- © 2011 American Heart Association, Inc.