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Global Translational Medicine Influence of estrogen on RV mitochondria in PH

inhibitor (U0126) prevented and reversed PH in male focus on examining the expressions of these mitochondrial
hypoxic rats, reducing both pulmonary pressure and RV genes in both animal models of PH and PAH patients
hypertrophy. All these studies suggested that ERK1/2 in both sexes at different RV stages (compensated and
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may be a therapeutic target in PAH. decompensated) through transcriptomic/proteomic
analysis and/or mass spectrometry and their molecular
6.6. Summary mechanisms in in vitro and in vivo preclinical studies
The expression of these above-mentioned genes in RV before the development of therapies for RV in PAH.
in PAH is summarized in Table 2 and the associated
molecular pathway is presented in Figure 2. Due to limited Acknowledgments
data on these E2- and mitochondria-related genes and None.
proteins and data mainly obtained from males (Table 2),
the role of each gene or protein in altering RV function Funding
in different sexes at different RV stages (compensated and This study was supported in part by the Engineering and
decompensated) in PAH is still unclear. More studies are Physical Sciences Research Council (EPSRC) Student
required to examine the mechanistic pathways in Figure 2 Excellence Award (SEA) Studentship (C.C.), Faculty
and their importance to RV function in PAH.
Start-Up Fund from the University of Strathclyde (L.T.),
7. Conclusions RSE Re-Boot (COVID-19 Impact) Research Grants
(L.T.), and the Academy of Medical Sciences Springboard
PAH is a sex dimorphism condition, with females being at Award (L.T.).
a higher risk than males. The mortality of PAH relies on the
status of the RV and has been associated with alterations in Conflict of interest
mitochondrial functions. E2 can regulate mitochondrial The authors declare no conflicts of interest.
biogenesis activity, influence mtDNA replication and
repair, as well as influence the balance of mitochondrial Author contributions
fusion/fission proteins. Restoring mitochondrial function
is expected to improve RV function in PAH. However, Conceptualization: Chelbi Coyle, Lian Tian
100
limited studies exist on these mitochondrial genes and the Writing – original draft: Chelbi Coyle
associated molecular pathways as discussed in this review. Writing – review & editing: All authors
Future studies are needed to determine the expressions of Ethics approval and consent to participate
these mitochondrial genes at different RV stages in PAH.
Transcriptomic and proteomic analysis are being used for Not applicable.
profiling including mitochondria- and E2-related genes
and proteins. 101,102 Mass spectrometry can be used to Consent for publication
reveal the levels of E2 in the RV. 75,102 Further studies are Not applicable.
also required to understand the exact mitochondrial genes,
proteins, and signaling pathways by which E2 targets and Availability of data
the E2-mitochondria interaction in RV in PAH of both Not applicable.
sexes in in vitro studies, in vivo preclinical studies, and
clinical investigation to identify druggable targets and References
develop promising therapeutics. Finally, PAH patients are
currently receiving the same treatments regardless of sex, 1. Humbert M, Guignabert C, Bonnet S, et al. Pathology and
pathobiology of pulmonary hypertension: State of the art
even though studies have shown that male and female PAH and research perspectives. Eur Respir J. 2019;53(1): 1801887.
patients respond to treatments differently. Therefore,
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personalized treatments based on sex could be taken into doi: 10.1183/13993003.01887-2018
consideration in the future. 2. Simonneau G, Montani D, Celermajer DS, et al.
Mitochondria play an important role in RV function, Haemodynamic definitions and updated clinical
but the molecular mechanisms for sex-dependent classification of pulmonary hypertension. Eur Respir J.
2019;53(1):1801913.
mitochondrial function and the role of estrogen
(especially E2) in RV in PAH are not well understood. In doi: 10.1183/13993003.01913-2018
addition, understanding the roles of E2 and its targeting 3. Prins KW, Thenappan T. World Health Organization
mitochondrial genes in RV function shall provide insight Group I pulmonary hypertension: Epidemiology and
into therapeutics for RV in PAH. Future studies should pathophysiology. Cardiol Clin. 2016;34(3):363-374.

Volume 3 Issue 3 (2024) 8 doi: 10.36922/gtm.2494