Abstract 16473: Loss of the Apelin-Apelin Receptor Signaling Axis Worsens Hemodynamic Alterations and Right Ventricular (rv) Adaptation and Abrogates 17ß-Estradiol (E2)-Mediated Protection in Experimental Pulmonary Arterial Hypertension (PAH)

Abstract

Introduction: Women are more likely to develop PAH but exhibit more favorable hemodynamics and better survival than men. These improved outcomes have been linked to protective effects of E2. We recently linked RV-protective effects of E2 to regulation of apelin signaling. However, the role of apelin and its receptor APJ in RV failure is unknown. Hypothesis: RV cardiomyocytes (RVCM)-derived apelin exerts beneficial effects on RV endothelial cells (RVECs). Apelin-APJ signaling is necessary for E2’s RV-protective effects. Methods: Apelin and APJ abundance were quantified (Western blot) and immunolocalized in RVs from PAH patients. In vivo , RV failure was induced in male Sprague-Dawley rats by pulmonary artery banding (PAB). A subset of PAB rats were treated with E2 ± APJ inhibitor ML221. Hemodynamics, RV function and molecular changes were assessed. To study the role of RVCM apelin, conditioned media was collected from RVCMs after apelin knockdown and then added to RVECs. In addition, conditioned media from untreated RVCMs was added to RVECs pretreated with ML221. Lastly, RVECs were treated with E2 ± siApelin or ML221. p<0.05 was considered statistically significant. Results: In PAH RVs, apelin and APJ localized to RVCMs and RVECs and were decreased vs controls (p<0.05). In PAB+E2+ML221 rats, inhibition of apelin signaling resulted in more RV hypertrophy and decreased RV function (p<0.05 vs sham or PAB+E2). Conditioned media from RVCMs+siApelin reduced RVEC eNOS phosphorylation, transwell migration and ring formation (p<0.05 vs scrambled control conditioned media). Concomitantly, treatment of RVECs with ML221 blocked transwell migration and ring formation induced by RVCM conditioned media (p<0.05 vs RVEC+veh control). Lastly, treatment of RVECs with siApelin or ML221 abrogated stimulatory effects of E2 on angiogenic function (p<0.05). Conclusions: Apelin and APJ are decreased in PAH-RVs and loss of apelin-APJ signaling results in more severe RV failure and abrogates E2-mediated RV protection. Apelin is secreted by RVCMs and exerts a beneficial paracrine effect on RVECs, where it is required for E2 to stimulate angiogenesis. Apelin-APJ signaling may represent a novel and therapeutically targetable, cell- and sex-specific signaling axis in the RV.