Elevated Plasma Oxidized Lipids in Severe Pulmonary Hypertension are Fully Restored by Estrogen Therapy

Abstract

Recently we reported that estrogen (E2) rescues pre-existing severe pulmonary hypertension (PH). PH is associated with pulmonary vascular remodelling. Vascular disorders result from complex interactions between oxidized-lipoproteins, monocytes/macrophages, injured endothelium and smooth muscle cells. Biological oxidation products of arachidonic acid, including prostaglandins (PGs), thromboxanes (TXs), hydroxyeicosatetraenoic acids (HETEs) and hydroxyoctadecadienoic acids (HODEs) play an important role in the pathogenesis of atherosclerosis, yet their role in PH is not fully known. Here we investigated whether PH is associated with increased plasma levels of oxidized-lipids, and if E2 can restore their levels. To induce PH, rats received monocrotaline (MCT, 60mg/kg, s.c.). Severe PH was established 21-days after MCT (PH, n=8). E2 (42.5ug/kg/day, s.c., n=6) was given from day-21 to 30. Saline treated rats served as control (CTRL, n=7). Cardiac catheterization was performed terminally to record RV-pressure (RVP). Plasma HODEs, HETEs, TXs and PGs were determined by mass-spectrometry. p<0.05 was considered significant. Values were mean±SE. Rats developed severe PH [RVP=68±2 vs. 31±2 mmHg in CTRL, p<0.01). E2 rescued PH (RVP=38±1 mmHg, p<0.01 vs. PH). PH was associated with increased plasma levels (ng/ml of plasma) of 9-HODE (2217±381 vs. 949±255 in CTRL, p<0.05) and 13-HODE (4347±439 vs. 1871±609 in CTRL, p<0.05). E2 reversed PH-induced increase in HODEs (9-HODE=976±259; 13-HODE=2469±531; all p<0.05 vs. PH). PH led to significantly elevated plasma 5-HETE (938±77 vs. 663±15), 12-HETE (9720±972 vs. 6633±522) and 15-HETE (818±62 vs. 534±7; all p<0.05 vs. CTRL). E2 fully reversed the increase in HETEs (5-HETE=708±37; 12-HETE=6981±248; 15-HETE=622±50; p<0.05 vs. PH). PH also led to elevated plasma TXB2 (3.5±0.2 vs. 2.8±0.1), PGD2 (98±11 vs. 35±7) and PGE2 (27±1 vs. 13±2; all p<0.05 vs. CTRL) and E2 restored their levels (TXB2=2.6±0.2; PGD2=54±10; PGE2=19±2; all p<0.05). In conclusion, severe PH is associated with increased plasma levels of oxidized lipids that are fully restored by E2.