Mineralocorticoid receptors in pulmonary hypertension and right heart failure: From molecular biology to therapeutic targeting

Abstract

Pulmonary hypertension (PH) is a devastating condition characterized by pulmonary vascular remodelling, leading to progressive increase in pulmonary artery pressure and subsequent right ventricular failure. Aldosterone and the mineralocorticoid receptor (MR), a nuclear transcription factor, are key drivers of cardiovascular disease and MR antagonists are well-established in heart failure. Now, a growing body of evidence points at a detrimental role of MR in PH. Pharmacological MR blockade attenuated PH and prevented RV failure in experimental models. Mouse models with cell selective MR deletion suggest that this effect is mediated by MR in endothelial cells. While the evidence from experimental studies appears convincing, the available clinical data on MR antagonist use in patients with PH is more controversial. Integrated analysis of clinical data together with MR-dependent molecular alterations may provide insights why some patients respond to MRA treatment while others do not. Potential ways to identify MRA ‘responders’ include the analysis of underlying PH causes, stage of disease, or sex, as well as new biomarkers.

Introduction

Pulmonary hypertension (PH) is a devastating condition characterized by pulmonary vascular remodelling, leading to progressive increase in pulmonary artery pressure, subsequent right ventricular (RV) failure, and premature death (Maron et al., 2021; Zolty, 2020). PH is defined by a mean pulmonary artery pressure greater than or equal to 20 mmHg at rest, which combines heterogeneous pulmonary vascular conditions classified into five groups as follows: Group 1 — pulmonary arterial hypertension (PAH), including idiopathic, heritable and drug/toxin-induced PH; Group 2 — PH due to left heart disease; Group 3 — PH due to lung disease and/or chronic hypoxia; Group 4 — PH due to chronic thromboembolism; and Group 5 — PH with unclear multi-factorial mechanisms (Simonneau et al., 2019). The initial changes in the development of PH are characterized by endothelial cell dysfunction, apoptosis, increased oxidative stress and an upregulation of adhesion molecules (Jurasz, Courtman, Babaie, & Stewart, 2010; Rabinovitch, Guignabert, Humbert, & Nicolls, 2014; Thompson & Lawrie, 2017). As a result of endothelial cell dysfunction, immune cells infiltrate the pulmonary vascular wall and further exaggerate pulmonary vascular remodelling (Rabinovitch et al., 2014). Pulmonary vascular remodelling in PH is characterized by progressive thickening of the intimal and medial layer of distal arterioles due to augmented proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), pulmonary artery adventitial fibroblasts, and possibly endothelial-mesenchymal transdifferentiation of pulmonary arterial endothelial cells (PAECs). Increased extracellular matrix deposition and media thickening leads to vascular stiffening, increased pulmonary vascular resistance, and elevated pulmonary artery pressure (Jurasz et al., 2010; Thompson & Lawrie, 2017). Consequently, increased afterload induces structural and functional changes of the RV, eventually resulting in RV failure, which is associated with adverse outcome (Al-Omary, Sugito, Boyle, Sverdlov, & Collins, 2020; Maron et al., 2021; Nathan et al., 2019; van der Bruggen, Tedford, Handoko, van der Velden, & de Man, 2017). While primary PAH is relatively rare, PH and associated RV remodelling may occur secondary to common cardiopulmonary diseases, including left heart disease, lung diseases such as chronic obstructive pulmonary disease or interstitial lung diseases (Al-Omary et al., 2020; Nathan et al., 2019).

Despite extensive research in this field, the mechanisms underlying the development and progression of PH remain incompletely understood. Current therapies target the endothelin, nitric oxide (NO), and prostacyclin pathways, which have been identified to contribute to the pathogenesis of PAH (Galie et al., 2016; Thompson & Lawrie, 2017). However, these therapies predominantly aim to resolve pulmonary vasoconstriction rather than structural vascular remodelling (Thompson & Lawrie, 2017). In addition, there are still no approved treatment strategies available for PH due to left heart failure or lung diseases, which account for a large proportion of patients with PH (Al-Omary et al., 2020; Galie et al., 2016; Nathan et al., 2019; Thompson & Lawrie, 2017). Therapeutic targeting of a number of recently identified signalling pathways that are dysregulated in PH has been or is currently evaluated in preclinical and early clinical trials (Prins et al., 2019; Toshner et al., 2020). Among these, mineralocorticoid receptor (MR) signalling has been identified as one of the underling mechanisms that determine pulmonary vascular remodelling and disease progression in PH (Maron & Leopold, 2015; Omidkhoda, Vakilian, Mohammadpour, Sathyapalan, & Sahebkar, 2020).

In this review, we summarize latest scientific insights that advance our understanding about the crucial role of MR signalling in pulmonary vascular and RV remodelling and evaluate whether MR antagonists may provide a new option for the management of PH and RV failure.