Abstract 230: Gender Differences in the Development of Experimental Pulmonary Hypertension and Associated Right Ventricular Remodeling: The Role of Estrogen Rescue
17-beta estradiol or Estrogen (E2) pre-treatment has been shown to attenuate the development of pulmonary hypertension (PH). Here, we aim to investigate the gender differences and the effect of ovariectomy on the development of experimental PH and adverse right ventricular (RV) remodeling. We also evaluate the therapeutic potential of E2 in rescuing PH and adverse RV remodelling in male and female rats. Male and female (intact and ovariectomized (OVX)) rats were treated with a single injection of monocrotaline (MCT, 60mg/kg, s.c.) to induce PH. Twenty one days after MCT, rats developed severe PH. At this point, one set of rats from each group was left untreated to develop PH-induced right ventricular failure (RVF), whereas the other set received E2 (42.5 ug/kg/day, 10-day slow release s.c. pellets). E2-treated rats were observed for an additional 12 days after cessation of therapy to check whether the effects of therapy were long-lived. Saline treated rats served as control (CTRL). Serial echocardiography was performed to monitor cardiopulmonary hemodynamics. Direct RV catheterization was terminally performed to record RV peak systolic pressure (RVPSP). The expression of novel extracellular matrix (ECM) enzymes A Disintegrin And Metalloproteinase (ADAM15 and 17) and Osteopontin (OPN) were assessed by RT-PCR. Intact females developed less severe PH than males and OVX females at day 30 (RVPSP: Females=62±3, Males=74±3, OVX=77±3 mm Hg, p<0.05 vs. respective CTRL). E2 therapy resulted in rescue of PH in all groups (RVPSP: Females=36±4, Males=38±2, OVX=44±2 mm Hg, p<0.05 vs. respective PH-RVF). Intact females also developed less severe RV remodeling compared to males and OVX females. Expression of OPN increased ∼7-9-fold in PH-RVF males and OVX but only ∼2-fold in intact females, (p<0.05 vs. CTRL for all). E2 reversed OPN upregulation in all groups (p<0.05 vs. PH-RVF). Novel ECM-degrading Disintegrin-Metalloproteinases ADAM15 and ADAM17 transcripts were also elevated ∼2-fold in all PH-RVF animals (p<0.05 vs. CTRL). E2-therapy reversed RV remodeling in all groups (p<0.05 vs. PH-RVF). In conclusion, intact females are more protected against the development of PH compared to males and OVX females. E2 rescues PH and adverse RV remodeling in all groups.
- © 2012 by American Heart Association, Inc.