Influence of estrogen on right ventricular mitochondrial function in pulmonary hypertension

Coyle, Chelbi and MacLean, Margaret R. and Tian, Lian (2024) Influence of estrogen on right ventricular mitochondrial function in pulmonary hypertension. Global Translational Medicine, 3 (3). 2494. (https://doi.org/10.36922/gtm.2494)

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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.

ORCID iDs

Coyle, Chelbi, MacLean, Margaret R. and Tian, Lian ORCID logoORCID: https://orcid.org/0000-0002-9699-8009;
CORE (COnnecting REpositories)