title: Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats.
abstract: Pulmonary arterial hypertension (PH) is a deadly disease characterized by pulmonary arterial vasoconstriction and hypertension, pulmonary vasculature remodeling, and right ventricular hypertrophy. Our previous in vivo studies, performed in several models of cardiac, vascular, and/or renal injury, suggest that the metabolites of 17beta-estradiol may inhibit vascular and cardiac remodeling. The goal of this study was to determine whether 2-methoxyestradiol (2ME), major non-estrogenic estradiol metabolite, prevents the development and/or retards the progression of monocrotaline (MCT)-induced PH. First, a total of 27 male Sprague Dawley rats were injected with distillated water (Cont, n=6) or monocrotaline (MCT; 60 mg/kg, i.p.; n=21). Subsets of MCT animals (n=7 per group) received 2ME or its metabolic precursor 2-hydroxyestradiol (2HE; 10 microg/kg/h via osmotic minipumps) for 21 days. Next, an additional set (n=24) of control and MCT rats was monitored for 28 days, before right ventricular peak systolic pressure (RVPSP) was measured. Some pulmonary hypertensive animals (n=8) were treated with 2ME (10 microg/kg/h) beginning from day 14 after MCT administration. MCT caused pulmonary hypertension (ie, increased right ventricle/left ventricle+septum [RV/LV+S] ratio and wall thickness of small-sized pulmonary arteries, and elevated RVPSP) and produced high and late (days 22 to 27) mortality. Pulmonary hypertension was associated with strong proliferative response (PCNA staining) and marked inflammation (ED1+cells) in lungs. Both metabolites significantly attenuated the RV/LV+S ratio and pulmonary arteries media hypertrophy and reduced proliferative and inflammatory responses in the lungs. Furthermore, in diseased animals, 2ME (given from day 14 to 28) significantly decreased RVPSP, RV/LV+S ratio and wall thickness, and reduced mortality by 80% (mortality rate: 62.5% vs. 12.5%, MCT vs. MCT+2ME day 14 to 28). This study provides the first evidence that 2ME, a major non-estrogenic, non-carcinogenic metabolite of estradiol, prevents the development and retards the progression of monocrotaline-induced pulmonary hypertension. Further evaluation of 2ME for management of pulmonary arterial hypertension is warranted.
authors.affiliation: Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, and the VA Pittsburgh Health System, Pittsburgh, PA 15219-3138, USA. tofovic@dom.pitt.edu
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
authors.forename: Eman M
authors.initials: EM
authors.lastname: Salah
authors.forename: Hussam H
authors.initials: HH
authors.lastname: Mady
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Mona F
authors.initials: MF
authors.lastname: Melhem
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D007150:Immunohistochemistry; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D016686:Monocrotaline; C001390:2-hydroxyestradiol