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Influence of estrogen on right ventricular mitochondrial function in pulmonary hypertension

Chelbi Coyle1 ,  Margaret R. MacLean1 ,  Lian Tian1*
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1 Strathclyde Institute of Pharmacy and Biomedical Sciences, Faculty of Science, University of Strathclyde, Glasgow, United Kingdom
Global Translational Medicine 2024, 3(3), 2494 https://doi.org/10.36922/gtm.2494
Submitted: 21 December 2023 | Accepted: 29 May 2024 | Published: 28 August 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

There is a female predominance in pulmonary arterial hypertension (PAH) with a ~4:1 female-to-male ratio. However, female PAH patients exhibit better right ventricular (RV) function and thus better survival than the males. The majority of the current PAH therapies target pulmonary vascular remodeling and/or vasoconstriction in the pulmonary vasculature. However, no therapies directly target the RV, partially because the underlying mechanisms of RV failure in PAH are not fully understood. Since the RV serves as the main determinant of mortality, clarifying the mechanism of RV failure and the associated sex differences in PAH may promote the development of novel therapeutic strategies. Numerous molecular abnormalities have been detected in RV in PAH, particularly due to the suppression of mitochondrial function, including the inhibition of glucose oxidation and a shift to uncoupled aerobic glycolysis (Warburg metabolism) and excessive mitochondrial fission. The mitochondrial suppression is associated with hypocontractility and increased apoptosis in RV cardiomyocytes, and the hyperproliferative, pro-fibrotic, and apoptosis-resistant phenotypes in RV fibroblasts in PAH. Mitochondria also serve as the site for sex steroid synthesis, and in turn, the sex steroids, particularly estradiol (E2), influence the mitochondria both indirectly and directly. It is not well understood how E2 affects mitochondrial function in RV in PAH. Hence, this review focuses on the key mitochondrial genes and proteins that are influenced by PAH, E2, and sex.

Keywords
Estradiol
Pulmonary arterial hypertension
Right ventricle
Mitochondria
Sex differences
Funding
This study was supported in part by the Engineering and Physical Sciences Research Council (EPSRC) Student Excellence Award (SEA) Studentship (C.C.), Faculty Start-Up Fund from the University of Strathclyde (L.T.), RSE Re-Boot (COVID-19 Impact) Research Grants (L.T.), and the Academy of Medical Sciences Springboard Award (L.T.).
Conflict of interest
The authors declare no conflicts of interest.
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Global Translational Medicine, Electronic ISSN: 2811-0021 Print ISSN: 3060-8600, Published by AccScience Publishing
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