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Global Translational Medicine Influence of estrogen on RV mitochondria in PH

Table 1. Pulmonary hypertension (PH) groups as classified coupling, lower RV mass, and better diastolic adaptation in
by the World Health Organization (WHO) female PAH patients than the males. In addition, females
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also reportedly respond better to approved PAH therapies
Group Definition than males. Hence, there is a critical need to understand
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Group 1 Pulmonary arterial hypertension the sexual dimorphism in PAH and the underlying
Group 2 Pulmonary hypertension due to left heart disease mechanisms.
Group 3 Pulmonary hypertension due to lung diseases and/or hypoxia The sex paradox is also known as the estrogen paradox.
Group 4 Pulmonary hypertension due to pulmonary artery Endogenous estrogens, particularly, estradiol (E2) and
obstructions its metabolites, are thought to play an important role in
Group 5 Pulmonary hypertension with unclear and/or pulmonary vascular remodeling and thus, cause more
multifactorial mechanisms
women to develop PAH. 21-23 One example of sex difference
Note: Adapted from reference Humbert et al 2 is related to the mutation of the gene encoding bone
morphogenetic protein receptor 2 (BMPR2). BMPR2
with overt features of venous/capillaries involvement, and mutation can result in loss of the BMPR2 function and
persistent PH of the newborn syndrome. 2 may lead to PAH. It has been reported that females have
PAH is a rare disease with an estimated prevalence of a higher penetrance of the BMPR2 mutation (40%) versus
around 5 – 52 cases/million. Although rare, PAH is a fatal males (14%). 23,24 A mutation in the BMPR2 gene is found
3
disease with high mortality. More than 30 years ago, one in 80% of heritable PAH patients and approximately
registry reported 1-year survival rate of 68% and 5-year 20% of idiopathic PAH patients. 25-27 In addition, E2 may
survival rate of 34% in patients with heritable PAH. As predispose women to PAH as E2 signaling leads to a
4
more treatments are developed and the management reduction in BMPR2 function in normal pulmonary artery
of PAH is improved, the estimated 1-year and 5-year smooth muscle cells (PASMCs) without BMPR2 mutation
survival rates have improved to ~86 – 90% and 61 – 65%, and drives a pro-proliferative phenotype in the PASMCs,
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respectively, based on recent registries on PAH and an potentially resulting in the development of PAH.
5-7
estimated 1-year survival rate of 94% and 10-year survival Although the higher incidence rate of PAH in females is
rate of 60% in another recent registry on PAH associated probably related to E2, E2 on the other hand, is thought
with connective tissue disease. At present, the mortality to have beneficial and protective effects on RV, leading to
8
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rate of PAH patients remains high and better therapeutics better RV function in female PAH patients than the males.
One evidence is that exogenous E2 administered through
are needed.
subcutaneous pellets demonstrates a protective role within
In PAH, the pathology begins with an obstructive the RV and, thus, enhances survival in the Sugen/hypoxia
vasculopathy in the pulmonary circulation. As a result, (SuHx) animal model of PH. However, recent clinical
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many studies and therapeutic development have focused trials of anastrozole to lower estrogen levels in PAH patients
on the pulmonary vasculature. However, the prognosis in did not demonstrate any effect on RV function, suggesting
PAH is mainly determined by the response of the RV to that endogenous estrogen was neither protective nor
the RV pressure overload, with RV failure accounting as pathogenic pathogenic ( ; unpublished data from Kawut
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the major cause of death in PAH patients. At present, et al.) The effects of endogenous and exogenous E2 on
9,10
most PAH therapies only target the pulmonary vasculature cardiopulmonary function require more studies.
component, with no therapies directly and effectively The effects of estrogen on RV function in PAH may be
targeting the RV. Since RV is the major determinant of partially attributed to its interaction with mitochondria.
mortality, it has thus been of great interest in recent years. During the progression of PAH, mitochondria in the
Note that when assessing the response of RV to increased RV undergo metabolic changes, notably mitochondrial
RV afterload, RV function alone such as RV contractility fragmentation (fission) and a shift toward uncoupled
is not sufficient, rather RV-pulmonary artery coupling is a aerobic glycolysis, known as the Warburg metabolism. 31-34
better metric to assess the cardiopulmonary function and Mitochondrial metabolic function has been proposed
provide prognosis. 11-13 Another important fact in PAH is the to be linked to many observed molecular abnormalities
sex paradox. PAH predominantly affects females in which in the RV and the resulting RV dysfunction including
there is a ~4:1 female-to-male ratio. 14-17 Although female reduced contractility and increased fibrosis. Therefore,
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sex represents a clinical risk factor, male PAH patients studying mitochondrial function in RV in PAH has been
have worse survival rates particularly due to poorer RV of great interest to reveal the underlying mechanisms
status and hemodynamic profiles. 11,18-20 This is evidenced for developing novel, promising therapeutics. E2 has
by higher RV contractility and RV-pulmonary artery been known to interact with mitochondrial function

Volume 3 Issue 3 (2024) 2 doi: 10.36922/gtm.2494