Both estrogen receptor subtypes, α and β, attenuate cardiovascular remodeling in aldosterone salt-treated rats

Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart disease requires more precise information on the role of both estrogen receptor (ER) subtypes, ER alpha and ER beta. Therefore, we determined whether selective activation of ER alpha or of ER beta would confer redundant, specific, or opposing effects on cardiovascular remodeling in aldosterone salt-treated rats. The ER alpha agonist 16 alpha-LE2, the ER beta agonist 8 beta-VE2, and the nonselective estrogen receptor agonist 17 beta-estradiol lowered elevated blood pressure, cardiac mass, and cardiac myocyte cross-sectional areas, as well as increased perivascular collagen accumulation and vascular osteopontin expression in ovariectomized rats receiving chronic aldosterone infusion plus a high-salt diet for 8 weeks. Uterus atrophy was prevented by 16 alpha-LE2 and 17 beta-estradiol but not by 8 beta-VE2. Cardiac proteome analyses by 2D gel electrophoresis, mass spectrometry, and peptide sequencing identified specific subsets of proteins involved in cardiac contractility, energy metabolism, cellular stress response and extracellular matrix formation that were regulated in opposite directions by aldosterone salt treatment and by different estrogen receptor agonists. We conclude that activation of either ER alpha or ER beta protects the cardiovascular system against the detrimental effects of aldosterone salt treatment and confers redundant, as well as specific, effects on cardiac protein expression. Nonfeminizing ER alpha agonists such as 8 beta-VE2 have a therapeutic potential in the treatment of hypertensive heart disease.