Abstract 20654: An Estrogen Receptor α (ERα)-BMPR2-Apelin Axis Mediates 17β-Estradiol’s Protective Effects on Right Ventricular Function in Experimental Pulmonary Hypertension (PH)
Introduction: Women with pulmonary arterial hypertension (PAH) exhibit superior RV function and survival compared to men, a phenomenon attributed to poorly understood cardioprotective effects of 17β-estradiol (E2).
Hypothesis: E2, through ERα, attenuates PH-induced right ventricular (RV) dysfunction by up-regulating the pro-contractile and anti-apoptotic peptide apelin. This ERα-mediated increase in apelin is mediated by the myocardial remodeling effector bone morphogenetic protein receptor 2 (BMPR2).
Methods: BMPR2 and apelin were measured (western blot) in RVs from patients with PAH-induced RV failure and in RV homogenates from male or female Sprague-Dawley rats with sugen/hypoxia (SuHx)-, monocrotaline (MCT)- or hypoxia-induced PH (HPH). H9c2 rat cardiomyoblasts and isolated RV-cardiomyocytes were stressed with TNF-α (10 ng/ml) or staurosporine (50 nM) ± E2 (100 nM; 24hrs). ERα-, BMPR2- and apelin-dependence were evaluated by siRNA (5 pmol). p<0.05 by ANOVA was considered significant.
Results: Apelin was decreased in RVs with maladaptive (SuHx-PH, MCT-PH) but not adaptive remodeling (HPH), suggesting cardioprotective effects. ERα localized to cardiomyocytes and correlated positively with BMPR2 and apelin expression in SuHx-RVs and human RVs. Treatment of SuHx-PH rats with E2 or ERα agonist increased RV BMPR2 and apelin, whereas RV apelin was decreased in E2-treated hypoxic ERα knockout mice (p<0.05), but not in ERβ knockout mice. In H9c2 cells, E2 or ERα agonist attenuated TNF-α- or staurosporine-induced decreases in BMPR2 or apelin (p<0.05 for all endpoints). E2 protection was lost in presence of siRNA directed against ERα, BMPR2, or apelin (p<0.05). ERα was necessary for E2-mediated increases in BMPR2 and apelin, and BMPR2 was required for the E2-mediated increase in apelin (p<0.05 for siRNA vs scramble). ChIP studies in E2-treated H9c2s revealed binding of ERα to the BMPR2 promoter.
Conclusions: E2, via ERα, increases BMPR2 and apelin in the failing RV and in stressed rat cardiomyoblasts. The E2-mediated increase in apelin is BMPR2-dependent and likely occurs through direct binding of ERα to the BMPR2 promoter. Harnessing this E2-ERα-BMPR2-apelin axis may lead to novel, RV-targeted therapies for PAH patients of either sex.
Author Disclosures: A. Frump: None. M. Albrecht: None. S. Brueils-Bonnet: None. J. Whitson: None. B. Yakubov: None. M. Brown: None. S. Provencher: None. S. Bonnet: None. T. Lahm: None.
- © 2016 by American Heart Association, Inc.