Abstract 5651: Apelin Deficient Mice Demonstrate Worsening Pulmonary Hypertension in a Nitric Oxide Dependent Manner
Recent studies have shown high expression of the GPCR APJ and its ligand apelin in the pulmonary vasculature. Given its known vasodilatory properties and pulmonary expression, we hypothesize that disruption of this pathway leads to worsening of pulmonary hypertension in the murine hypoxia model, and that the pathway is abnormally regulated in patients with pulmonary arterial hypertension (PAH). Right ventricular systolic pressures were assessed in apelin deficient (KO) mice after 2 weeks of hypoxia. Lungs were perfused with contrast agent (Microfil), and imaged using micro-computed tomography (CT) imaging. We measured NO levels in the serum and evaluated the lungs for expression of endothelial nitric oxide synthase (eNOS) using quantitative real-time polymerase chain reaction (RT-PCR) and western blots. We found that apelin KO mice developed more severe pulmonary hypertension in response to hypoxia compared to wildtype mice (34.1 vs. 28.3 mmHg, p<0.001). Micro-CT of the lungs demonstrated vascular abnormalities in the apelin KO mice including pruning of smaller vessels and increased tortuosity of the larger vessels. Apelin KO mice had decreased levels of serum NO (p=0.02) and had lower expression of eNOS in the lungs, as determined by RT-PCR and western blots. We also performed ELISA assays to determine apelin levels in patients with PAH. Apelin levels from PAH patients were significantly lower compared to healthy controls (1.25 vs. 0.89 ng/mL, p=0.037). These data suggest that disruption of apelin signaling can exacerbate pulmonary hypertension, and identify this pathway as a potential therapeutic target for treatment of this refractory human disease.