2-Methoxyestradiol in Pulmonary Arterial Hypertension: A New Disease Modifier

Tofovic, Stevan P.; Jackson, Edwin K.

doi:10.5772/intechopen.86812

Cited by 4 publications

(8 citation statements)

References 164 publications

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“…As in the previous hypoxia model, female sex is protective in the rat model of MCT-PH and ovariectomy aggravates PH while exogenous administration of estrogens, in both males and females, improves RV function (Tofovic et al, 2006;Umar et al, 2011). Estradiol metabolites such as 2 ME or 2hydroxyestradiol are able to prevent and retard the progression of MCT-induced PH in rats by attenuating pulmonary vascular remodeling and RV hypertrophy, and reducing proliferative and inflammatory responses in the lungs (Tofovic et al, 2005;Tofovic et al, 2010). The use of an ERα agonist rescued MCT-PH and protected RV myocardium by restoring RV apelin and bone morphogenetic protein receptor type 2 (BMPR2) (Frump et al, 2021).…”

Section: Evidence From Experimental Animal Models Of Pulmonary Arterial Hypertensionmentioning

confidence: 88%

“…A detailed description of sex hormone metabolism and signaling, published elsewhere (Austin et al, 2013;Lahm et al, 2014;Lahm and Kawut, 2017;Tofovic and Jackson, 2019;Tofovic and Jackson, 2020), is beyond the scope of this review. Briefly, the three main estrogenic steroids are 17-β estradiol (estradiol or E2), the primary active sex hormone in the female, estrone (E1) and estriol (E3).…”

Section: Overview Of Sex Hormones Synthesis and Metabolismmentioning

confidence: 99%

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Sex Differences in Pulmonary Hypertension

Rodríguez-Arias

García‐Álvarez

2021

Front. Aging

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Pulmonary hypertension (PH) includes multiple diseases that share as common characteristic an elevated pulmonary artery pressure and right ventricular involvement. Sex differences are observed in practically all causes of PH. The most studied type is pulmonary arterial hypertension (PAH) which presents a gender bias regarding its prevalence, prognosis, and response to treatment. Although this disease is more frequent in women, once affected they present a better prognosis compared to men. Even if estrogens seem to be the key to understand these differences, animal models have shown contradictory results leading to the birth of the estrogen paradox. In this review we will summarize the evidence regarding sex differences in experimental animal models and, very specially, in patients suffering from PAH or PH from other etiologies.

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Section: Evidence From Experimental Animal Models Of Pulmonary Arterial Hypertensionmentioning

confidence: 88%

Section: Overview Of Sex Hormones Synthesis and Metabolismmentioning

confidence: 99%

Sex Differences in Pulmonary Hypertension

Rodríguez-Arias

García‐Álvarez

2021

Front. Aging

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“…The angiogenic properties of E2 are in striking contrast to the strong antiangiogenic effects of its major non-estrogenic metabolite 2ME. The other biological effects of 2ME relevant to PAH (Figure 2) have been reviewed previously [166].…”

Section: Opposing Effects Of E2 and 2me On Angiogenesis (Key Role Of mentioning

confidence: 99%

“…2ME, via a multitude of actions (Figures 2 and 3), can not only provide pulmonary vascular and RV protection, but also oppose the potential detrimental effects of E2 due to redirection of its own metabolism and metabolism of AA in PAH. Thereby, 2ME could be considered as both mediator and corrector of E2 s action and a new disease modifier in PAH [166].…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Tofovic

Jackson

2019

IJMS

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Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH.

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“…Finally, 2ME not only mediates (at least in part) the beneficial effects of estradiol in PH, but also 2ME exhibits opposing effects to estradiol on several processes relevant to the underlying pathophysiology of PH, including angiogenesis, metabolic reprograming, inflammation, and immunity [12]. Therefore, recently we suggested that 2ME should be viewed as a disease modifier in women with PH [20]. The objective of this study was to examine the preventive and curative effects of 2ME in chronic hypoxia (CH)-induced PH in male rats.…”

Section: Introductionmentioning

confidence: 97%

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

Tofovic

Zhang

et al. 2021

Prilozi

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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.

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2-Methoxyestradiol in Pulmonary Arterial Hypertension: A New Disease Modifier

Cited by 4 publications

References 164 publications

Sex Differences in Pulmonary Hypertension

Sex Differences in Pulmonary Hypertension

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

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

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