Abstract 18581: Genistein Rescues Severe Pulmonary Hypertension and Right Ventricular Failure In Mice
Introduction: Phytoestrogens have been shown to reverse endothelial dysfunction in the murine model. Pre-treatment and long-term administration of a common dietary substance such as genistein, a phytoestrogen, have been shown to prevent the development of pulmonary arterial hypertension (PAH) and associated right ventricular (RV) dysfunction. We hypothesized that administration of genistein once the disease is established would rescue monocrotaline (MCT)-induced PAH and RV dysfunction.
Methods: Chronic PAH with associated RV failure was induced in 2–3 month old male C57BL/6 mice by a single intraperitoneal injection of 60 mg/kg MCT (n= 8) or saline (CTRL, n=3). After 21 days, when PAH had already established, subcutaneous genistein therapy was started in one group (n=4) at a dose of 1 mg/kg/day for 9 days. All of the animals were sacrificed at day 30. Serial echocardiography was performed once a week in the first three weeks and every three days in the last 9 days to measure cardiac function. Direct cardiac catheterization was performed right before euthanasia to measure RV peak systolic pressure (RVPSP). RV, LV and septum were isolated to measure RV hypertrophy index (RV/(LV+septum)) and lung weight was assessed. Values were mean±SE and p<0.05 was considered significant.
Results: At day 30, MCT group developed PAH with RVPSP of 71±4 mmHg compared to 30±2 mmHg in CTRL (p<0.05). RV hypertrophy was also evident in MCT group as RV/(LV+septum) increased significantly from 0.22±0.2 in CTRL to 0.7±0.08 in MCT (p<0.05). MCT group also developed RV failure with RV ejection fraction (RVEF) of 32±2% in MCT vs. 62±2% in CTRL (P<0.05). Lung weight was increased in MCT compared to CTRL (0.21±0.001 g in MCT vs. 0.15±0.02 g in CTRL, p<0.05). Genistein treatment for 9 days reversed PAH by: 1) attenuating RVPSP to 33±0.9 mmHg compared to 71±4 mmHg in MCT (p<0.05), 2) reversing RV failure by improving RVEF of 62±2 % compared to 34±2 % in MCT (p<0.05), 3) decreasing lung weight to 0.16±0.01g compared to 0.21±0.001g in MCT (p<0.05), and 4) reversing RV hypertrophy with RV/(LV+septum) of 0.26±0.01 compared to 0.7±0.08 in MCT (p<0.05).
Conclusion: Genistein rescues severe PAH and RV failure by improving RV function, decreasing RV pressure and lung weight, and reversing RV hypertrophy.
- © 2010 by American Heart Association, Inc.