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Global Translational Medicine Influence of estrogen on RV mitochondria in PH

to a lesser extent in the skin, liver, adipose tissue, and This was associated with increased aromatase activity and
brain. Cholesterol undergoes a series of reactions, which as a result, elevated levels of circulating E2 in both male
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are mediated largely by members of the cytochrome P450 (64%) and female (36%) portopulmonary hypertension-
(CYP) family and the key estrogen synthase, aromatase, PAH patients.
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allowing E2 to be formed. The mitochondria are also the
site for E2 biosynthesis and contain many of the required 6.2. PGC-1α
enzymes. Even when E2 is administered exogenously, it PGC-1α, located in the cell nucleus and cytoplasm, is a
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is preferentially translocated to the mitochondria. The versatile transcription coactivator. It has been shown
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high fluidity of the mitochondria membranes and the to be predominantly expressed in tissues in which the
lipophilic nature of E2 allow for it to diffuse easily into mitochondria are most abundant, such as the RV. Here,
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the mitochondria. Thus, the mitochondria essentially act it interacts with a variety of transcription factors that
as an “E2 sink”. On the other hand, E2 helps to maintain play a role in many responses including those involved
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low levels of ROS, thereby protecting mitochondria from in mitochondrial biogenesis. 81,82 The exact mechanism by
oxidative damage. If the mitochondria become damaged, which PGC-1α achieves this is still being studied; however,
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this will inhibit E2 biosynthesis leading to a decline in E2 it has been shown to involve NRF1/2 and signaling through
levels and an increase in ROS production, which, further, the estrogen-related receptor α (ERRα). The relationship
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accelerates mitochondrial dysfunction. 36 between PGC-1α and the NRF system is considered to
be major as PGC-1α directly and dramatically modulates
6. Estradiol (E2) levels and the regulated NRF1/2 gene expression and its downstream gene, TFAM,
mitochondria-associated genes in PAH the key gene involved in mtDNA replication and repair.
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6.1. Circulating E2 levels Meanwhile, mutated NRF1 can equally inhibit PGC-1α-
stimulated cell proliferation. Particularly, within the RV,
The normal circulating E2 level is 43 – 113 pmol/L for PGC-1α has been found to be significantly reduced in
healthy males aged between 26 – 77 years. Male PAH male MCT and SuHx rats and ovariectomized female SuHx
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patients display an increase in E2 levels when compared rats and displays a decreasing trend in RV of limited PAH
with control subjects in several clinical studies: 154 versus patients. 67,84,85 Reduced PGC-1α level is associated with
106 pmol/L, 78 versus 59 pmol/L, and 150 versus impaired mitochondrial and RV function in male SuHx
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102 pmol/L, respectively. While, in pre-menopausal rats and ovariectomized female SuHx rats 67,84,85 and the
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women, the normal circulating E2 level is 275 – 1650 treatment with E2 before the induction of PAH preserved
pmol/L, and in post-menopausal women, this falls PGC-1α level and mitochondrial and RV function in the
to < 40 pmol/L. Meanwhile, in pregnant women, E2 levels female SuHx rats. 67
can increase to as much as 26 nmol/L. Pre-menopausal
women with PAH illustrated higher levels of E2 and PGC-1α is also involved in other systems that influence
shorter 6-min walking distances when compared with mitochondrial activity including the fission and fusion
healthy controls. Interestingly, tricuspid annular plane events. The dynamin-like GTPases mitofusin 1 and
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systolic excursion (TAPSE) fluctuated depending on the 2 (MFN1/2) are responsible for mediating the fusion
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menstrual cycle. In addition, E2 was shown to influence (joining) of the mitochondria. PGC-1α is able to induce
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the transcription of extracellular vesicle miRNA-21, MFN2 transcription with the help of binding to ERRα.
miRNA-29c, and miRNA-376a, which promote vascular Furthermore, the ability of PGC-1α to induce mitochondrial
proliferation and are implicated in the pathobiology of biogenesis has been linked to MFN2 expression, with the
PAH. 77 loss of MFN2 reducing PGC-1α activity. 86,87 Female PAH
patients and female SuHx and MCT rats with MFN2 and
Post-menopausal women with PAH have demonstrated PGC-1α deficiencies have been correlated to mitochondrial
higher levels of E2 compared with healthy controls. dysfunction including a notable shift to excessive fission in
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These PAH patients also had shorter 6-min walking PASMCs. Meanwhile, overexpression of MFN2 has been
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distances, worse RV afterload, RV dilatation, and overall found to reduce the rates of cell proliferation, enhance
RV function. Similarly in males, worse RV function was apoptosis, and reverse mitochondrial fragmentation in
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found to be linked to higher levels of E2 and reduced PASMCs both in vitro and in vivo. In addition, MFN2 has
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dehydroepiandrosterone sulfate (DHEAS) levels. 76 also been found to be downregulated in male SuHx rats,
One of the major E2 production enzymes, aromatase which is associated with mitochondrial dysfunction and
(CYP91A1), was found to contain a single-nucleotide RV cardiomyocyte hypertrophy. Therefore, PGC-1α is a
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polymorphism (SNP) in the CYP19A1 gene (rs7175922). potential therapeutic target for RV in PAH.
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Volume 3 Issue 3 (2024) 6 doi: 10.36922/gtm.2494