Abstract 18888: 2-Methoxyestrone Retards the Progression of Angioproliferative Pulmonary Hypertension in Rats - Role of 17beta-Hydroxysteroid Dehydrogenase Pathway
Background: 2-Methoxyestradiol (2ME2; major non-estrogenic metabolite of estradiol) attenuates monocrotaline (MCT)- and SU5416+hypoxia (SU/Hx)-induced pulmonary arterial hypertension (PH). 2ME2 is dehydrogenated by type-2 17β-hydroxysteroid dehydrogenase (17-HSD2) to 2-methoxyestrone (2ME1), a metabolite with no biological activity. However, in vivo 2ME1 may be converted back to 2ME2 by type-1 17β-HSD (17-HSD1). Our recent study indicates that 2ME-2 and all-trans retinoic acid (atRA; a 17HSD1 inducer) have synergistic therapeutic effects in MCT-induced PH.<
Methods: To study the role of 17β-HSD metabolic pathway on development of PH, first we examined the effects of 2-ME1 on proliferation of human pulmonary artery smooth muscle cells (hPASMC), lung fibroblasts (hLF) and hela cells, in the presence or absence of atRA. Next, in male rats, we studied the effects of 2ME1 on progression of MCT-induced PH (Day14-28 post MCT). Finally, we investigated the effects of 2ME1 on SU/Hx-induced PH. Ten days into hypoxia, intact (F) and ovariectomized (OVX) female rats were implanted minipumps delivering vehicle (PEG-400 0.5μl/h; F-SU and OVX-SU groups) or 2-ME1 (20μg/kg/h; F-2ME1 and OVX-2ME1 groups)
Results: In hPASMC, hLF and hela cells 2ME1 had no/modest antimitogenic effect at a high pharmacological concentration, whereas in the presence of atRA, 2ME1 exhibited strong and concentration-dependent inhibition of cells growth. In male rats, 2ME1 retarded the progression of MCT-PH, and attenuated right ventricle (RV) and pulmonary vascular remodeling. In female rats SU/Hx induced severe angioproliferative PAH (RVPSP: F=23+2 vs F-SU = 116+10mmHg) and 2ME1 reduced PAH. Ovariectomy attenuated PAH (RVPSP: F-SU= 116+10 vs F-2ME1=96+10mmHg and in OVX-SU rats 2ME1 significantly retarded the progression of disease (RVPSP: OVX-SU= 99+9 mmHg vs. OVX-2ME1= 71+4) and markedly reduces RV remodeling (RV/LV+S: OVX-SU=0.715+0.021 vs. OVX-2ME1=0.555+0.026; p<0.001)
Conclusions: This study provides the first evidence that in vivo 2ME1 is biologically active and has therapeutic effects in angioproliferative PAH. Presented data suggest that 17β-HSD pathway of estradiol metabolism may play significant role in development and/or progression of PH.
Author Disclosures: J. Hu: None. O. Rafikova: None. F. Schneider: None. E.K. Jackson: Ownership Interest; Modest; Co-inventor on US patent: Use of Estradiol Metabolites for treatment of Pulmonary Hypertension. S. Tofovic: Ownership Interest; Modest; EKJ and SPT are co-inventors on US patent: Use of Estradiol Metabolites for Treatment of PAH.
- © 2015 by American Heart Association, Inc.