Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ERα), attenuates PAH-induced RV failure (RVF) by up-regulating the pro-contractile and pro-survival peptide apelin via a bone morphogenetic protein receptor 2 (BMPR2)-dependent mechanism. We report that ERα and apelin levels are decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ERα agonist. Studies employing ERα or ERβ null mice, ERα mutant rats or siRNA demonstrated that ERα is necessary for E2 to upregulate RV apelin. E2 and ERα increased BMPR2 in PH-RVs and in isolated RV cardiomyocytes, associated with ERα binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to enhance pro-survival signaling. E2 or ERα agonist rescued monocrotaline-PH and restored RV apelin and BMPR2 expression. We identified a novel cardioprotective E2-ERα-BMPR2-apelin axis in the RV. Harnessing this axis may lead to novel, RV-targeted therapies for PAH patients of either sex.
Andrea L. Frump, Marjorie E. Albrecht, Bakhtiyor Yakubov, Sandra Breuils Bonnet, Valerie Nadeau, Eve Tremblay, Francois Potus, Junichi Omura, Todd Cook, Amanda Fisher, Brooke E. Rodriguez, R. Dale Brown, Kurt R. Stenmark, C. Dustin Rubinstein, Kathy Krentz, Diana M. Tabima, Rongbo Li, Xin Sun, Naomi C. Chesler, Steeve Provencher, Sebastien Bonnet, Tim Lahm