Abstract 16762: Genetic Ablation or Molecular Inhibition of NEDD9 Prevents Vascular Fibrosis and Pulmonary Arterial Hypertension in vivo

In pulmonary arterial hypertension (PAH), vascular fibrosis increases pulmonary vascular resistance (PVR) to promote right ventricular (RV) dysfunction. However, effective treatments targeting vascular fibrosis in PAH do not exist. Our network analysis predicted that the pro-metastatic protein NEDD9 is a novel mediator of vascular fibrosis. To validate this finding, human pulmonary artery endothelial cells (HPAECs) were treated with vehicle (V) control or the pro-fibrotic PAH hormone aldosterone (ALDO)(10 -7 mol/L) for 24 hr and transfected with si-scrambled control (si-Scr) or si-NEDD9. Compared with V-treated cells, ALDO induced 3-D collagen gel contraction, which was inhibited significantly by si-NEDD9 (7.0 ± 1.0 [V] vs. 11 ± 1.5 [ALDO] vs. 11.6 ± 0.5 [ALDO + si-Scr] vs. 8.0 ± 0.5 mm [ALDO + si-NEDD9], P in vivo . To accomplish this end, wild type (WT) and NEDD9 -/- mice were injected with Sugen-5416 (20 mg/kg) once weekly and exposed to hypoxia (10% FiO 2 ) for 21 d (N=5-9/condition). Fibrosis (58 ± 3 vs. 74 ± 7 % pulmonary arterial collagen, P -/- -SU-5416/Hypoxia compared to WT-SU-5416/Hypoxia mice as assessed by trichrome staining, catheterization, and Fulton index, respectively. In a second PAH model, rats were injected with monocrotaline (MCT)(60 mg/kg) and treated with V control or Staramine-mPEG labeled with si-NEDD9 (1.5 mg/kg dose x3) (N=5-7/condition). Compared to MCT, NEDD9 expression was decreased by 50% (P -4 ) in MCT-si-NEDD9, which corresponded to a 60% (P in vivo , and may have important therapeutic implications for patients with fibrotic vascular diseases including PAH.