Novel Insights Into Estradiol Regulation of Right Ventricular Failure in Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease that, if left untreated, leads to pulmonary vascular remodeling, right ventricular (RV) failure, and death. Women are more susceptible to the development of PAH; however, once they have disease, women with PAH exhibit better right ventricular (RV) function and survival than men. The underlying mechanisms driving this sex difference are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor alpha (ERα), attenuates PAH-induced RV failure (RVF) by up-regulating the pro-contractile and pro-survival peptide apelin. We found that ERα and apelin expression were decreased in RV homogenates from PAH patients with RV failure and from rats with maladaptive (but not adaptive) RV remodeling in sugen/hypoxia PH, monocrotaline PH, and pulmonary artery banding RV failure. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ERα 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 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin. We identified what we believe to be a novel cardioprotective E2/ER-α/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.