Abstract 1262: Selective Activation of Estrogen Receptor-α or Estrogen Receptor-β Attenuates Hypertension and Cardiac Hypertrophy in Aldosterone Salt Treated Rats
Introduction: Excessive aldosterone secretion results in hypertension and promotes cardiac remodelling including fibrosis and hyperthrophy. Results from the Framingham Study suggest that gender and hence estradiol influence aldosterone mediated cardiac hypertrophy whereas 17β-estradiol protects against cardiovascular damage in various animal models.
Hypothesis: We propose that selective activation of estrogen receptor α (ERα) and/or β (ERβ) will attenuate aldosterone mediated hypertension, cardiac hypertrophy and vascular inflammation.
Methods: We compared the effect of the non-selective estrogen receptor agonist 17β-estradiol (E2), the estrogen receptor-α agonist 16α-LE2 and the estrogen receptor-β agonist 8β-VE2 (n= 68 rats in total) on blood pressure (invasive hemodynamics), cardiac mass (ventricular weight, histo-morphometry), peri-vascular collagen and osteopontin expression (quantified by histo-morphology of cardiac and aortic sections) in ovarectomized aldosterone salt treated (AST) rats. Cardiac proteome analysis by 2D-DIGE was applied to identify specific target proteins indicating ERα or ERβ activation.
Results: E2, 16α-LE2 and 8β-VE2 reduced blood pressure (−11% p<0.05, −26% p<0.01 and 7minus;23% p<0.05 respectively vs. AST), heart weight (−10% p<0.05, −29% p<0.01 and −14% p<0.05 respectively vs. AST) as well as perivascular collagen accumulation and vascular osteopontin expression in AST rats. A total of 53 individual protein spots were down-regulated in AST compared to control rats (p<0.05). The ERα agonist 16α-LE2 ERβ restored the expression levels of 6 specific proteins whereas the ERβ agonist 8β-VE2 specifically up-regulated the expression of 8 individual proteins, all of which were suppressed in AST rats.
Conclusions: Activation of either estrogen receptor subtype antagonizes aldosterone mediated cardiovascular injury and results in specific alterations of the cardiac proteome. Subtype selective ER ligands are a novel tool to dissect specific functions of ERα and ERβ in heart disease and may possess superior pharmacological profile than non-selective agonists such as 17β-estradiol.