Mineralocorticoid receptors in pulmonary hypertension and right heart failure: From molecular biology to therapeutic targeting
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.
Section snippets
Biology of mineralocorticoid receptor signalling
The mineralocorticoid aldosterone is synthetized in the glomerular zone of the adrenal cortex as one of the effector hormones of the renin-angiotensin-aldosterone system (RAAS) (Jaisser & Farman, 2016; Lother, Moser, Bode, Feldman, & Hein, 2015). Aldosterone is synthesized from cholesterol in a series of catalytic reactions with two rate-limiting proteins: steroidogenic acute regulatory protein (StAR), which transports cholesterol to the inner mitochondrial membrane and aldosterone synthase
Aldosterone as a biomarker of pulmonary hypertension and right ventricular remodelling
Elevated levels of circulating aldosterone have been observed in different experimental models of PH (Aguero et al., 2014; Kowalski et al., 2021; Liu et al., 2017; Maron et al., 2012; Maron et al., 2014; Wang et al., 2020) and in patients with PAH (Calvier et al., 2016; Maron et al., 2013; Safdar et al., 2015) (Table 1). In treatment-naïve PAH patients, circulating levels of aldosterone were correlated with increased pulmonary vascular resistance and transpulmonary gradient and decreased
Mineralocorticoid receptor antagonists in experimental pulmonary hypertension
Several studies demonstrated the potential of MR antagonists to prevent or reverse PH and RV failure in rodent models (Boehm et al., 2018; Kowalski et al., 2021; Preston et al., 2013) (Menon et al., 2021) (Table 2). Concomitant treatment with spironolactone or eplerenone attenuated media thickening of pulmonary arteries and pulmonary hypertension in response to chronic hypoxia (Boehm et al., 2018; Kowalski et al., 2021; Menon et al., 2021; Preston et al., 2013). Similar findings were obtained
Mineralocorticoid receptor signalling in pulmonary artery endothelial cells
As outlined above, plasma aldosterone levels are increased in patients with PH and in animal models of pulmonary hypertension. In patients with left heart failure, increased transpulmonary aldosterone concentrations indicate that pulmonary synthesis of aldosterone contributes to the circulating aldosterone levels (Maron et al., 2016). In addition to the increased circulating levels of aldosterone, locally increased aldosterone concentrations in lung tissue as observed in rats after combined use
Mineralocorticoid receptor signalling in pulmonary artery smooth muscle cells
Numerous studies imply a role for MR in PASMCs for the pathophysiology of PH. Hypoxia, aldosterone, and PDGF have been shown to promote nuclear translocation and subsequent activation of MR in PASMCs in vitro, resulting in increased PASMC proliferation (Preston et al., 2013) (Fig. 2). Interestingly, in PASMCs from patients with PAH but not secondary PH, BMP2 and BMP7 increased proliferation was associated with an upregulation of MR (Yamanaka et al., 2010). Additionally, aldosterone has been
Regulation of mineralocorticoid receptor signalling in the right ventricle
The beneficial effects of MR antagonists on PH in mice were associated with improved RV remodelling (Boehm et al., 2018; Kowalski et al., 2021; Preston et al., 2013). This raised the question whether these were directly mediated by inhibition of MR in cardiac cells or indirectly by decreasing RV afterload. Suggesting more RV-directed adverse effects of aldosterone. Increased MR expression in RV tissue has been observed in various animal models of RV remodelling, including pulmonary artery
Clinical studies on mineralocorticoid receptor antagonists in pulmonary hypertension and right ventricular failure
Based on the results of these preclinical studies and considering the use of MR antagonists in left heart failure, several retrospective clinical studies have evaluated a potential benefit of MR antagonists in various forms of PH patients (Table 3). For example, a retrospective analysis of spironolactone use in the Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicentre, Efficacy Study (ARIES)-1 and −2 trials showed a trend towards improved 6-min walking
Summary and perspectives
In summary, there is a growing body of evidence from preclinical studies suggesting that aldosterone and MR contribute to the pathophysiology of PH (Fig. 3). PH adds to a still growing list of conditions that are associated with deleterious MR signalling, such as heart failure, atherosclerosis, valvular heart disease, and diabetes mellitus, as well as chronic kidney, lung, or liver disease (Jaisser & Farman, 2016; Lother, 2020). Pharmacological MR blockade attenuated PH and subsequently
Declaration of Competing Interest
A.L. received fees for lectures and/or serving on advisory boards from AstraZeneca and Bayer not related to this work. A.M. and L.H. declare no conflict of interest.
Acknowledgments
This work is part of SFB1425, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation #422681845).
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