Abstract-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- (ER) protects the females from left ventricular hypertrophy, we treated male and female ER-deficient (ER Ϫ/Ϫ ) 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 (ϩ16%) heart weight/tibia length ratios compared with WT females (ϩ7%) at 6 weeks. In ER Ϫ/Ϫ mice, this situation was reversed. Female WT mice had the greatest heart weight/tibia length ratio increases of all of the groups (ϩ23%), even greater than ER Ϫ/Ϫ males (ϩ10%). Echocardiography revealed concentric left ventricular hypertrophy in male WT mice, whereas ER Ϫ/Ϫ females developed dilative left ventricular hypertrophy. The hypertrophic response in female ER Ϫ/Ϫ mice was accompanied by the highest degree of collagen deposition, indicating maladaptive remodeling. ER ϩ/ϩ females showed robust protective p38 and extracellular signal-regulated kinase 1/2 signaling relationships compared with other groups. Calcineurin A expression and its positive regulator myocyte-enriched calcineurin-interacting protein 1 were increased in deoxycorticosterone acetate-salt female ER Ϫ/Ϫ mice, yet lower than in WT males. Endothelin increased murine cardiomyocyte hypertrophy in vitro, which could be blocked by estradiol and an ER agonist. We conclude that a functional ER 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. Key Words: estrogen receptor-, heart Ⅲ hypertrophy Ⅲ fibrosis Ⅲ calcineurin Ⅲ p38 MAPK Ⅲ ERK1/2 F emales seem to be relatively protected from cardiovascular disease on the basis of animal and human studies; estrogens could play a role. 1-3 Clinical trials using estrogens for improving cardiovascular health were disappointing, perhaps because of poor estrogen receptor (ER) isoform selectivity and specificity. 4 The 2 functional isoforms, ER␣ and ER, are expressed in the myocardium. 5 Receptor-mediated effects of estrogens on cardiomyocyte biology are injury or stimulus dependent, 4,6 which, in turn, implicates activation of distinct, sex-dependent, signaling pathways and gene expression programs. 7 We described recently a sex-specific dimorphism in cardiac adaptation in response to deoxycorticosterone acetate (DOCA)-salt and showed that this response was independent of blood pressure. 8 Male mice developed left ventricular hypertrophy (LVH) that was linked to activation of a calcineurin-dependent pathway, which increased proinflammatory and profibrotic responses. In contrast, female DOCA mice maintained their initial physiological adaptive cardiac phenotype despite mineralocorticoid and...