<abstract xmlns="http://www.w3.org/1999/xhtml"><p>Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development of PH and that some of the biological effects of E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective of this study was to examine effects of 2ME in chronic hypoxia (CH)-induced PH and alpha-naphthylthiourea (ANTU)-induced acute lung injury and PH. In addition, we investigated the effects of exposure to different levels of CH on development of PH. Chronic exposure to 15% or 10% oxygen produced similar increases in right ventricle peak systolic pressure (RVPSP) and pulmonary vascular remodeling, but oxygen concentration-dependent increase in hematocrit. Notably, right ventricle (RV) hypertrophy correlated with level of hypoxia and hematocrit, rather than with magnitude of RVPSP. The latter suggests that, in addition to increased afterload, hypoxia (via increased hematocrit) significantly contributes to RV hypertrophy in CH model of PH. In CH-PH rats, preventive and curative 2ME treatments reduced both elevated RVPSP and pulmonary vascular remodeling. Curative treatment with 2ME was more effective in reducing hematocrit and right ventricular hypertrophy, as compared to preventive treatment. Single ANTU injection produced lung injury, i.e., increased lungs weight and induced pleural effusion. Treatment with 2ME significantly reduced pleural effusion and, more importantly, eliminated acute mortality induced by ANTU (33% vs 0%, ANTU vs. ANTU+2ME group). Chronic treatment with ANTU induced PH and RV hypertrophy and increased lungs weight. 2-ME significantly attenuated severity of disease (i.e., reduced RVPSP, RV hypertrophy and pulmonary vascular injury). This study demonstrates that 2ME has beneficial effects in chronic hypoxia- and acute lung injury-induced PH and provides preclinical justification for clinical evaluation of 2ME in pulmonary hypertension.</p></abstract>

Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development of PH and that some of the biological effects of E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective of this study was to examine effects of 2ME in chronic hypoxia (CH)-induced PH and alpha-naphthylthiourea (ANTU)-induced acute lung injury and PH. In addition, we investigated the effects of exposure to different levels of CH on development of PH. Chronic exposure to 15% or 10% oxygen produced similar increases in right ventricle peak systolic pressure (RVPSP) and pulmonary vascular remodeling, but oxygen concentration-dependent increase in hematocrit. Notably, right ventricle (RV) hypertrophy correlated with level of hypoxia and hematocrit, rather than with magnitude of RVPSP. The latter suggests that, in addition to increased afterload, hypoxia (via increased hematocrit) significantly contributes to RV hypertrophy in CH model of PH. In CH-PH rats, preventive and curative 2ME treatments reduced both elevated RVPSP and pulmonary vascular remodeling. Curative treatment with 2ME was more effective in reducing hematocrit and right ventricular hypertrophy, as compared to preventive treatment. Single ANTU injection produced lung injury, i.e., increased lungs weight and induced pleural effusion. Treatment with 2ME significantly reduced pleural effusion and, more importantly, eliminated acute mortality induced by ANTU (33% vs 0%, ANTU vs. ANTU+2ME group). Chronic treatment with ANTU induced PH and RV hypertrophy and increased lungs weight. 2-ME significantly attenuated severity of disease (i.e., reduced RVPSP, RV hypertrophy and pulmonary vascular injury). This study demonstrates that 2ME has beneficial effects in chronic hypoxia- and acute lung injury-induced PH and provides preclinical justification for clinical evaluation of 2ME in pulmonary hypertension.

2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

University of Pittsburgh School of Medicine

Department of Pharmacology and Chemical Biology

University St Cyril and Methods School of Medicine

PRILOZI

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that...

2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

Published Online: Apr 23, 2021

Page range: 41 - 51

DOI: https://doi.org/10.2478/prilozi-2021-0003

Keywords
Pulmonary hypertension, 2-methoxyestradiol, hypoxia, polycythemia, vascular remodeling, right ventricle, alpha-naphthylthiourea

© 2021 Stevan P. Tofovic et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

Published Online: Apr 23, 2021

Page range: 41 - 51

DOI: https://doi.org/10.2478/prilozi-2021-0003

KeywordsPulmonary hypertension, 2-methoxyestradiol, hypoxia, polycythemia, vascular remodeling, right ventricle, alpha-naphthylthiourea

© 2021 Stevan P. Tofovic et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
Pulmonary hypertension, 2-methoxyestradiol, hypoxia, polycythemia, vascular remodeling, right ventricle, alpha-naphthylthiourea