Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats

J Cardiovasc Pharmacol. 2005 Oct;46(4):430-7. doi: 10.1097/01.fjc.0000175878.32920.17.

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.

MeSH terms

  • 2-Methoxyestradiol
  • Animals
  • Blood Pressure / drug effects
  • Body Weight / drug effects
  • Cell Proliferation / drug effects
  • Disease Progression
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / physiopathology
  • Hypertension, Pulmonary / prevention & control*
  • Hypertrophy, Right Ventricular / chemically induced
  • Hypertrophy, Right Ventricular / pathology
  • Hypertrophy, Right Ventricular / prevention & control
  • Immunohistochemistry
  • Lung / chemistry
  • Lung / drug effects
  • Lung / physiopathology
  • Male
  • Monocrotaline
  • Proliferating Cell Nuclear Antigen / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Tubulin Modulators / pharmacology

Substances

  • Proliferating Cell Nuclear Antigen
  • Tubulin Modulators
  • Estradiol
  • 2-Methoxyestradiol
  • Monocrotaline
  • 2-hydroxyestradiol