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Global Translational Medicine Influence of estrogen on RV mitochondria in PH

both directly through targeting the mitochondria and abnormalities are correlated with reduced RV contractility
indirectly through the nucleus. However, the role of E2 and increased RV stiffness resulting in reduced RV systolic
36
in sex-dependent mitochondrial and RV function in PAH and diastolic function and RV-pulmonary artery coupling
is not well understood. In this review, we will summarize in animal models of both PH and PAH. Hence, we propose
the molecular pathways through which E2 affects that normalizing mitochondrial metabolism could improve
mitochondrial function and the expression of genes and RV function and RV-pulmonary artery coupling through
proteins in these pathways in the RV in PAH. The role of increasing RV contractile function and reducing cell
the E2 metabolites is beyond the scope of this review and proliferation and collagen production in RV fibroblasts.
will not be discussed. This has been demonstrated in PAB, MCT, Fawn-Hooded,
and SuHx rat models of PH. 29,32,43,45-48 These abnormalities
2. Sex differences in mitochondrial function have been observed in both RV myocytes and fibroblasts. It
in RV in PAH is unknown whether RV myocytes or fibroblasts (or other
cell types) are more sensitive to changes in mitochondrial
Under normal circumstances, the mitochondria generate function or hormones. However, the loss of RV contractile
energy in the form of adenosine triphosphate (ATP) function is known to be at least partly due to a decrease
through oxidative phosphorylation. In many PAH cases, in mitochondrial respiration in the RV myocytes and
mitochondrial abnormalities result in reduced ATP probably an increase in RV stiffness, given that normalizing
production, which is synthesized predominantly through mitochondrial respiration or metabolism can improve RV
glycolysis. Clinically, mitochondrial metabolic changes can contractile function and RV compliance by reducing cell
be detected by an increase in glucose uptake as measured proliferation and collagen production in RV fibroblasts in
through 2-deoxy-2-[ F]-fluoro-D-glucose (FDG) animal models of PH. 29,42,45-47
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uptake. 33,37-39 In addition, an increase in fatty acid utilization
as indicated with iodine-123-beta-methyl iodophenyl Note the animal model of PH discussed above focused
pentadecanoic acid (BMIPP) 40,41 or [ F]-fluoro-6-thia- on the males and did not include the females to examine
18
heptadecanoic acid (FTHA), has been observed in the the sex differences. Glucose transporter 1 (GLUT1) is a key
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RV in PAH patients. This indicates a shift toward glycolysis regulator and marker for glucose utilization. GLUT1 was
and fatty acid oxidation, which are key hallmarks of shown to increase in the RV of male MCT, Fawn-Hooded,
mitochondrial dysfunction. However, possible differences and PAB rats and associated with increased glycolysis
32,46,47
in glucose uptake or fatty acid oxidation between male when compared to their respective controls. A study
and female PAH patients and associated RV changes on SuHx rat RV found an increase in GLUT1 expression
29
have not been investigated, probably due to the limited only in the females but not in the males. The reason for
the difference in RV GLUT1 expression between SuHx
number of PAH patients. As glucose uptake or fatty acid rat model and other rat models of PH is not clear. Other
utilization is inversely correlated to RV function 33,37,38,40 mitochondrial metabolisms such as fatty acid metabolism
and female patients have better RV function than males, also play an important role in RV function in PAH. In
it might be expected that mitochondrial metabolism is addition, the RV of female SuHx rats is in a compensated
better preserved in the RV of female PAH patients and sex stage rather than a more severe or failure stage in male
is involved in the mitochondrial abnormalities in PAH- SuHx and MCT rats. Studies on mitochondrial metabolism
associated RV failure, although this needs to be confirmed at different stages (i.e., compensated and decompensated)
clinically. of RV in both sexes and the associated RV function and
RV mitochondrial abnormalities have also been RV-pulmonary artery coupling in PAH may shed light on
demonstrated in animal models of PH. Monocrotaline the role of different mitochondrial changes in different
(MCT) rats display mitochondrial depolarization, animal models of PH and be useful for the development
increased mitochondrial fission, and a shift to glycolysis of therapeutics.
in RV. 42-44 In other animal models of PH including SuHx
rats, Fawn-Hooded rats, and rats with pulmonary artery 3. Estrogen receptors
banding (PAB), there is also a shift toward glycolysis in Cholesterol serves as the precursor molecule for E2
the RV. 32,45-47 Interestingly, while a shift toward fatty acid synthesis. The downstream reactions are then catalyzed
oxidation was observed in the RV myocytes in SuHx and predominantly by the cytochrome P450 enzymes and
PAB rats, 45,47 there is a decrease in fatty acid oxidation in aromatase. Once synthesized, E2 will mediate its signaling
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the RV myocytes in Fawn-Hooded rats. Glutaminolysis through coupling to one of its three receptors: estrogen
46
is less studied and has been seen to increase in RV in receptor alpha (ERα, ESR1), estrogen receptor beta (ERβ,
MCT rats. These studies have shown that mitochondrial ESR2), and G protein-coupled estrogen receptor (GPER or
48

Volume 3 Issue 3 (2024) 3 doi: 10.36922/gtm.2494