Abstract 17749: Rescue of Established Pulmonary Hypertension by a High Density Lipoprotein Mimetic Peptide
INTRODUCTION Vascular disorders involve complex interactions between oxidized lipids, macrophages, smooth muscle cells and endothelium. Pulmonary hypertension (PH) is characterized by pulmonary vascular remodelling and oxidative stress. As PH patients have lower plasma HDL, we hypothesized that an HDL mimetic peptide 4F may rescue established PH in rats.
METHODS Rats received single injection of monocrotaline (MCT, 60mg/kg, s.c.) or PBS (CTRL, n=10) at day 0. From day 21-30, MCT rats either received 4F (4F, 50mg/kg/day, s.c., n=10) or left untreated to develop severe PH (PH, n=10). Echocardiography and RV catheterization were used to evaluate cardiopulmonary hemodynamics. Lung macrophages were stained with ED1. Fibrosis was determined by trichrome staining. Oxidation products of arachidonic and linoleic acids and eicosanoids including hydroxyoctadecadienoic acid (HODE), hydroxyeicosatetraenoic acid (HETE), thromboxanes (TX) and prostaglandins (PG) were measured in plasma by mass spectrometry. Human pulmonary artery smooth muscle cell (hPASMC) proliferation in vitro was assessed by MTT assay.
RESULTS Severe PH was evident at day 30 in PH group [RVP=74±1 vs. 29±1 mmHg; RV/(LV+IVS)=0.68±0.05 vs. 0.23±0.02; RV ejection fraction (RVEF)=28±1 vs. 65±1%, p<0.05 vs. CTRL]. Plasma levels of oxidized lipids were significantly increased in PH compared to CTRL ((pg/ml of plasma) 9-HODE=2597±175 vs. 1205±224; 13-HODE=5135±571 vs. 2017±504; 5-HETE=777±24 vs. 672±14; 12-HETE=10597±289 vs 7326±473; and 15-HETE=719±43 vs 549±11; p<0.05 vs CTRL for all). PH group also had elevated plasma TXB2 (3±0.3 vs 2.2±0.1), PGD2 (64±4 vs 34±6) and PGE2 (23±2 vs 13±2; all p<0.05 vs. CTRL). Interestingly 4F was very efficient in reversing adverse cardiopulmonary structure (fibrosis and alveolar macrophages) and function (RVP=46±3 mmHg, RV/LV+IVS= 0.38±0.02, RVEF=51±3%, all p<0.05 vs PH). 4F also suppressed plasma oxidized lipids (9-HODE=1491±336 pg/ml; 13-HODE=2678±654; 5-HETE=656±35; 12-HETE=9052±347 and 15-HETE=618±19), as well as TXB2 (1.8±0.2) and PG (PGD2=39±8 and PGE2=17±1) (p<0.05 vs. PH for all). In vitro, 4F (100ng/ml) inhibited hPASMC proliferation by 60% (p<0.05 vs CTRL).
CONCLUSIONS HDL mimetic peptide 4F rescues pre-existing severe PH in rats.
- © 2012 by American Heart Association, Inc.