Page 11 - GTM-3-3

Global Translational Medicine

REVIEW ARTICLE
Influence of estrogen on right ventricular

mitochondrial function in pulmonary
hypertension

Chelbi Coyle, Margaret R. MacLean , and Lian Tian*

Strathclyde Institute of Pharmacy and Biomedical Sciences, Faculty of Science, University of
Strathclyde, Glasgow, United Kingdom

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
*Corresponding author:
Lian Tian as the site for sex steroid synthesis, and in turn, the sex steroids, particularly estradiol
(lian.tian@strath.ac.uk) (E2), influence the mitochondria both indirectly and directly. It is not well understood
Citation: Coyle C, MacLean MR, how E2 affects mitochondrial function in RV in PAH. Hence, this review focuses on the
Tian L. Influence of estrogen on key mitochondrial genes and proteins that are influenced by PAH, E2, and sex.
right ventricular mitochondrial
function in pulmonary hypertension.
Global Transl Med. 2024:3(3):2494. Keywords: Estradiol; Pulmonary arterial hypertension; Right ventricle; Mitochondria; Sex
doi: 10.36922/gtm.2494
differences
Received: December 21, 2023
Accepted: May 29, 2024
Published Online: August 28, 2024
Copyright: © 2024 Author(s). 1. Introduction
This is an Open-Access article
distributed under the terms of the Pulmonary hypertension (PH) is a progressive and life-threatening disease that is
Creative Commons Attribution characterized by a sustained increase in pulmonary artery pressure and subsequent
License, permitting distribution,
1
and reproduction in any medium, right ventricular (RV) dysfunction and failure. Hemodynamically, this condition can be
provided the original work is defined as a mean pulmonary artery pressure greater than 20 mmHg at rest. The World
2
properly cited. Health Organization (WHO) has categorized PH into five different groups (Table 1). In
2
Publisher’s Note: AccScience this review, we will focus on group 1, pulmonary arterial hypertension (PAH). PAH can
Publishing remains neutral with be further subcategorized into seven different subtypes: idiopathic PAH, heritable PAH,
regard to jurisdictional claims in
published maps and institutional PAH due to or associated with drugs and toxins, connective tissue disease, congenital
affiliations. heart disease, etc., PAH due to long-term response to calcium channel blockers, PAH

Volume 3 Issue 3 (2024) 1 doi: 10.36922/gtm.2494