17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin
Andrea L. Frump, … , Sebastien Bonnet, Tim Lahm
Andrea L. Frump, … , Sebastien Bonnet, Tim Lahm
Published January 26, 2021
Citation Information: J Clin Invest. 2021;131(6):e129433. https://doi.org/10.1172/JCI129433.
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Research Article Pulmonology Vascular biology

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

Abstract

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 (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were 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 ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α 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 exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.

Authors

Andrea L. Frump, Marjorie Albrecht, Bakhtiyor Yakubov, Sandra Breuils-Bonnet, Valérie Nadeau, Eve Tremblay, Francois Potus, Junichi Omura, Todd Cook, Amanda Fisher, Brooke 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

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Figure 11

E2 induces formation of PPARγ/β-catenin complexes and requires BMPR2 to increase apelin expression or ERK1/2 activation in cardiomyoblasts.

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E2 induces formation of PPARγ/β-catenin complexes and requires BMPR2 to ...
(A) H9c2 cardiomyoblasts were treated with E2 (100 nM) for 0, 4, or 24 hours and then immunoprecipitated with PPARγ antibody or rabbit IgG isotype control. Input control for each sample is indicated (bottom). Note formation of PPARγ/β-catenin complexes with E2 treatment at 4 and 24 hours. (B) Time course of siRNA knockdown of BMPR2 (5 nM) effects on apelin protein expression in E2-treated (100 nM) H9c2 rat cardiomyoblasts at baseline conditions. (C and D) Effects of BMPR2 knockdown on E2-mediated upregulation of apelin in stressed cardiomyoblasts. H9c2 cells were pretreated with E2 (100 nM, 24 hours) and then stressed with TNF-α (10 ng/ml, 8 hours; C) or staurosporine (stauro; 50 nM, 4 hours; D) with or without siRNA knockdown of BMPR2 (5 nM, 24 hours prior to E2). (E) Effects of BMPR2 knockdown on E2-mediated ERK1/2 activation in stressed cardiomyoblasts. Cells were pretreated with E2 (100 nM, 24 hours) and then treated with stauro (50 nM, 4 hours) with or without siRNA directed against BMPR2 (5 nM; 24 hours prior to E2 and stauro). Representative blots for 3 independent experiments shown in A and B–E. Densitometries include data from all experiments. Scr = scramble siRNA. *P < 0.05 versus Scr control, $P < 0.05 versus E2 by ANOVA with post hoc Tukey’s correction in B; *P < 0.05 versus TNF + E2 or Stauro + E2 by Student’s t test in C and D; *P < 0.05 versus Scr control, #P < 0.05 versus Stauro, $P < 0.05 versus E2-treated Stauro group by ANOVA with post hoc Dunnett’s correction in E. Error bars represent mean ± SEM; each data point represents 1 experiment or animal.