Apolipoprotein-A1 Mimetic Peptide 4F Rescues Severe Pulmonary Hypertension in Rats and Inhibits Human Pulmonary Artery Smooth Muscle Cell Proliferation In Vitro

Abstract

Pulmonary hypertension (PH) is a characterized by arterial obstruction resulting from proliferation of pulmonary artery smooth muscle and endothelial cells. Genetic deletion of apolipoprotein-A1 increases airway hyperresponsiveness, inflammation, and collagen deposition in the lung. Apolipoprotein-A1 mimetic peptide 4F protects endothelial function, causes vasodilation, decreases inflammation and oxidative stress in lungs, yet its role in treating PH and right ventricular (RV) dysfunction is not known. We hypothesized that 4F may rescue pre-existing severe PH. We also investigate the effects of 4F on human pulmonary artery smooth muscle cell (hPASMC) proliferation in vitro as a possible mechanism of rescue by 4F. Twenty three rats were randomly divided into 4-groups. PH was induced by monocrotaline (MCT, 60mg/kg, s.c.). Severe PH was well-established at day-21 (PH, n=6) that progressed to RV failure (RVF, n=6) by day-30. One MCT-group was treated with 4F (50mg/kg/day, s.c., n=6) from day-21 to 30. Saline-treated rats served as control (CTRL, n=5). Serial echocardiography was performed to monitor cardiopulmonary hemodynamics. Cardiac catheterization was performed terminally to record RV-pressure (RVP). hPASMCs proliferation was assessed by MTT-assay. p<0.05 was considered significant. Values were mean±SE. Rats developed severe PH 21-days after MCT (RVP=67.12±1 vs. 29.8±1 mmHg in CTRL, RV/LV+IVS= 0.65±0.05 vs. 0.23±0.02, RV-ejection fraction (RVEF)= 40±1 vs. 65±1%, all p<0.05 vs. CTRL), which progressed to RVF by day-30 [RVP=74±1; RV/(LV+IVS)=0.68±0.05; RVEF=28.6±1%, p<0.05 for all vs. CTRL]. 4F-therapy from day-21 to 30 resulted in rescue of PH (RVP=47±3 mmHg, RV/LV+IVS= 0.38±0.02, RVEF= 51.7±3%, p<0.05 vs. PH and RVF). 4F also inhibited hPASMC proliferation (∼60% inhibition at 100ng 4F/ml medium, p<0.05). In conclusion, 4F rescues pre-existing severe PH and RV-dysfunction. Inhibition of PASMC proliferation may be one of the key mechanisms in this rescue.