Background— Cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in men and in women. Epidemiological studies indicate that estrogen replacement therapy is cardioprotective; the mechanisms involved in this process, however, are poorly understood. We therefore studied the effect of 17β-estradiol (E₂) on the development of pressure-overload hypertrophy.

Methods and Results— Ovariectomized mice receiving E₂ or placebo underwent transverse aortic constriction (TAC) or sham operation. TAC led to a significant increase in ventricular mass compared with sham operation. E₂ treatment reduced cardiac hypertrophy by 31% and 26% compared with placebo 4 and 8 weeks after TAC, whereas it had no effect on the degree of pressure overload, as determined by hemodynamic measurements. Furthermore, E₂ blocked the increased phosphorylation of p38-mitogen-activated protein kinase (MAPK) observed in the placebo-treated animals with TAC. No differences were observed in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 between the groups. E₂ had no effect on the expression of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor. Ventricular atrial natriuretic peptide (ANP) expression was detected only in the animals with TAC. Compared with placebo, E₂ treatment led to an increased expression of ANP in animals with pressure overload.

Conclusions— Here, we show that E₂ attenuates the hypertrophic response to pressure overload in mice. This observation demonstrates that hormone replacement therapy with E₂ has direct effects on the heart and may be beneficial in the treatment of postmenopausal women to reduce cardiac hypertrophy.