Abstract Background Pulmonary hypertension (PH) is a progressive and fatal disease characterized by increased pulmonary vascular resistance and right ventricular (RV) remodeling, ultimately leading to RV failure and death. Despite its clinical significance, there are no therapies directly targeting RV function. Apelin regulates cardiac development, angiogenesis, survival signaling, and vasodilation; however, its contribution to right ventricular remodeling in PH remains unclear. Hypothesis Apelin-mediated signaling promotes RV adaptative remodeling and survival through the inhibition of the Renin-angiotensin-aldosterone system (RAAS) and activation of Angiotensin converting enzyme 2 (ACE2). Methods To investigate the role of the Apelin-ACE2-RAAS axis, male and female rats were exposed to Sugen-hypoxia (SuHx) or normoxia to induce experimental PH. A subgroup of SuHx rats were treated with Pyr-Apelin-13 (200 ug/kg/day). RV hemodynamics were assessed, and RV tissues and isolated right ventricular endothelial cells (RVECs) were analyzed for structural changes by IHC and Apelin, angiotensin converting enzyme 1 (ACE1), ACE2, and angiotensin II type 1 receptor (AT1R) and mas receptor (MAS1) expression by quantitative RT-PCR and Western blotting. In vitro, RVECs were treated with Pyr-Apelin-13 (100 Nm, 24Hrs) alone or combined with the Apelin receptor (APLNR) antagonist (ML221, 100 µM, 24hrs) or ACE2 inhibitor (MLN-4760, 100 µM, 24hrs). Findings were corroborated with siRNA. Cellular functions of Normoxia, Suhx and SuHx+Apelin RVECs were assessed by using Matrigel tube formation (angiogenesis), scratch assay, and CCK-8 assays (cell viability). p 0.05 was considered statistically significant. Results Apelin treated SuHx rats demonstrated increased cardiac index, RV-PA coupling, and decreased RVSP, RV/LV+S, and collagen deposition compared to SuHx rats. RVECs from SuHx rats exhibited increased ACE1 and AT1R expression accompanied by decreased Apelin, ACE2 and MAS1, indicating dysregulated RAAS activation in PH. Apelin treatment restored ACE2 and MAS1 levels while suppressing ACE1 and AT1R expression, these effects were blocked by ML221 and MLN-4760, confirming ACE2-dependent signaling. Pyr-Apelin partially restored ring formation in SuHx RVECs and enhanced cell migration in wound-healing assays, whereas ACE2 (MLN4760) or APLNR (ML221) inhibition reduced migration. Similarly, Apelin increased cell survival, which was diminished by ML221 or ACE2 inhibition confirming that Apelin-mediated survival is dependent on APLNR and ACE2 signaling. Conclusions Apelin-ACE2 signaling mitigates PH-induced right ventricular remodeling by balancing RAAS activity, enhancing endothelial cell survival, migration, and angiogenesis. Our findings reveal the Apelin-ACE2-RAAS axis as a novel pathway controlling RV adaptation and suggest its potential as a therapeutic target to protect RV function in pulmonary hypertension. This abstract is funded by: NIH/NHLBI
Bharti et al. (Fri,) studied this question.