Abstract 15622: The Lipoxygenase Inhibitor Nordihydroguaiaretic Acid (NDGA) Prevents the Progression of Pulmonary Hypertension
Rationale: Pulmonary hypertension (PH) is a chronic lung disease characterized by severe pulmonary vascular remodeling. Recently we have shown increased circulating levels of oxidized fatty acids hydroxyoctadecadienoic acids (HODEs) and hydroxyeicosatetraenoic acids (HETEs) in PH. We hypothesized that HETEs and HODEs directly stimulate the proliferation of smooth muscle cells and their inhibition by lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) attenuates progression of PH.
Methods: Mice were placed in a hypoxic chamber (O2 ≤10%) for 21 days and either received daily treatments of NDGA (10mg/kg/day, i.p., n=4) from day 1, or left untreated to develop PH (n=7) . Untreated normoxic (n=8) mice served as controls. Cardiac catheterization was performed to record RV pressure (RVP) and RV hypertrophy index (RV/(LV+IVS)) was calculated. Pulmonary arteriolar thickening was assessed by staining lung tissue sections with Masson Trichrome staining . In vitro, human pulmonary artery smooth muscle cell (hPASMC) proliferation was assessed by MTT assay in the absence or presence of 12-HETE, 9-HODE and 13-HODE alone or together with NDGA.
Results: In vitro, 9-HODE, 13-HODE and 12-HETE treatment increased hPASMC proliferation 2-fold compared to untreated cells. NDGA inhibited the proliferative effects on hPASMC in a dose-dependent manner. In-vivo, NDGA treatment prevented the development of PH in hypoxic mice. RVP of hypoxic mice in the NDGA-treated group was significantly lower compared to untreated group (24.01±1.39 vs. 36.91±5.74, mmHg, p<0.05) and was comparable to normoxic mice (20.93±2.52 mmHg). RV hypertrophy index was elevated in the experimental hypoxic mice when compared to control mice (0.38±0.03 vs. 0.28±0.02 (p<0.001), while NDGA treatment prevented RV hypertrophy (0.28±0.04). Lung sections demonstrated increased arteriolar muscularization, which was prevented by NDGA therapy.
Conclusions: NDGA prevents the development of hypoxia-induced PH as well as smooth muscle cell proliferation induced by 9-HODE, 13-HODE and 12-HETE. We conclude that oxidized lipids play an important role in the development of PH.
- © 2013 by American Heart Association, Inc.