Abstract 20: Estrogen Receptor Beta is the Key Player in Rescue of Severe Pulmonary Hypertension by Estrogen
Introduction: Gender differences in experimental pulmonary hypertension (PH) are attributed to action of estrogen (E2). Pre-treatment with E2 prevents PH, but it is still unknown if E2 can rescue established PH. Most of the actions of E2 are mediated via E2 receptor alpha (ERa) and beta (ERb), which are both present in lung and heart. We hypothesize that E2 rescues severe PH by restoring lung and heart structure and function through ERb.
Methods: Male rats were treated with s.c. monocrotaline (MCT, 60 mg/kg, n=21) to induce PH. At day 21 when PH had established, one group was euthanized (MCT, n=6) and 3 other groups received either E2 (0.017 mg/day, n=6), ERb agonist DPN (0.34 mg/day, n=6) or ERa agonist PPT (0.34 mg/day, n=3) for 10 days. PBS treated rats were control (CTRL, n=6). Serial echocardiography was done to measure right ventricular (RV) function. RV systolic pressure (RVSP) was measured directly with a catheter just before sacrifice. Western Blot, real time PCR and histology were performed. P<0.05 was considered significant. Values were mean±SE.
Result: Severe PH was evident in MCT group at day 21 as RVSP was increased from 31±2 in CTRL to 69±2 mmHg in MCT (p<0.05). RV hypertrophy index (RV/(LV+IVS)) was increased from 0.22±0.001 to 0.64±0.07 whereas RV ejection fraction (RVEF) was reduced from 66±1.16 to 37±3%. Lung weight was increased from 1.4±0.1 to 2.4±0.1g, (all p<0.05) along with arteriolar medial hypertrophy. Starting E2 at day 21 reversed PH after 10 days as all of the above parameters were almost restored to CTRL levels (RVSP=38±2 mmHg), RV/(LV+IVS)=0.3±0.01, RVEF=62±1%, lung weight=1.8±0.1g) (all p<0.05 vs. MCT). Interestingly, DPN was as effective as E2 to rescue PH (RVSP=34±1 mmHg, RV/(LV+IVS)= 0.3±0.01, RVEF=64±4% and lung weight=1.5±0.4g) (all p<0.05 vs. MCT), whereas PPT was not as effective (RVPSP=56±1 mmHg, RV/(LV+IVS)=0.6±0.01, RVEF=40±4% and lung weight=2±0.1g). PCR of lungs showed that ERb transcripts, but not ERa, were significantly reduced in MCT and were restored by E2 (0.17±0.02 in MCT vs. 0.7±0.1 in E2, normalized to CTRL). ERb protein in lung and RV was also significantly reduced ∼2 fold in MCT and E2 restored ERb in both tissues.
Conclusion: E2 restores pulmonary and cardiac structure and function in severe PH through activation of ERb.
- © 2010 by American Heart Association, Inc.