Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension

Abstract

Pulmonary vascular disease, including pulmonary arterial hypertension (PAH), is increasingly recognized to be affected by systemic alterations including up‐regulation of the renin‐angiotensin‐aldosterone system and perturbations to metabolic pathways, particularly glucose and fat metabolism. There is increasing preclinical and clinical data that each of these pathways can promote pulmonary vascular disease and right heart failure and are not simply disease markers. More recently, trials of therapeutics aimed at neurohormonal activation or metabolic dysfunction are beginning to shed light on how interventions in these pathways may affect patients with PAH. This review will focus on underlying mechanistic data that supports neurohormonal activation and metabolic dysfunction in the pathogenesis of PAH and right heart failure as well as discussing early translational data in patients with PAH.

Abbreviations

BMI

body mass index

BMPR2

bone morphogenetic protein receptor type 2

CTEPH

chronic thromboembolic pulmonary hypertension

CTGF

connective tissue growth factor

DCA

dichloroacetate

ET‐1

endothelin

FC

functional class

iPAH

idiopathic PAH

MR

mineralocorticoid receptor

NYHA

New York Heart Association

NOX4

NADPH oxidase type‐4

oxLDL

oxidized LDL

PASMC

pulmonary artery smooth muscle cells

PAH

pulmonary arterial hypertension

PH

pulmonary hypertension

PVR

pulmonary vascular resistance

RAAS

renin‐angiotensin‐aldosterone system

RV

right ventricle

StAR

steroidogenic acute regulatory protein

XPB

xeroderma pigmentosum group B complementing protein

[¹⁸F]DG

Fludeoxyglucose

1. INTRODUCTION

Pulmonary hypertension (PH) is a highly morbid condition that can be caused by a variety of factors including destructive parenchymal lung disease with hypoxia, left atrial hypertension, chronic thromboemboli, or primary pulmonary vascular disease, so‐called pulmonary arterial hypertension (PAH). There is accumulating basic and clinical evidence that PH and PAH are more accurately described as syndromes. Indeed, neurohormonal and metabolic dysregulation can play a role in promotion and progression of disease in both cases. Further, there is emerging data on clinical use of drugs targeting these derangements in PAH patients. This review will focus on the underlying data that metabolic and neurohormonal disease can promote PAH and right heart adaptation to this condition and that targeting these molecular changes with potential interventions may be beneficial in PAH.

2. NEUROHORMONAL ACTIVATION IN PULMONARY HYPERTENSION: THE RENIN‐ANGIOTENSIN‐ALDOSTERONE SYSTEM (RAAS)

Classically, activation of RAAS begins with a decline in cardiac output that decreases afferent renal arterial blood. This event is detected by baroreceptors in the juxtaglomerular apparatus of the distal convoluted tubules, which release the aspartic protease protein and enzyme https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2413. The principal function of renin is to hydrolyse angiotensinogen (secreted from the liver) to generate https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=583. Angiotensin I is cleaved enzymically by https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1613 into angiotensin II (https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2504) through the removal of two C‐terminal residues occurring mainly in pulmonary arterial endothelial cells. In turn, AngII functions as an endocrine, paracrine, and intracrine hormone with pleiotropic effects, including up‐regulation of vasopressin release from the CNS and induced vascular smooth muscle cell contraction in the pulmonary and systemic arterial and venous circuits. Additionally, AngII stimulates adrenal zona glomerulosa cells to release https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2872, which is a mineralocorticoid hormone that binds to the https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=626 (MR) in renal epithelial cells to promote Na²⁺ and water retention, and K⁺ and Mg²⁺ excretion. Importantly, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2872 is also now an established vasoactive peptide that stimulates the MR in pulmonary endothelial cells to induce hypertrophic and fibrotic pulmonary arterial remodelling in PAH. The pathogenetic events related to RAAS in the context of pulmonary vascular disease are discussed here in detail.

2.1. Aldosterone, vascular remodelling, and PAH

Overactivation of RAAS is an emerging contributor to the pathogenesis of pulmonary vascular disease. Levels of circulating plasma aldosterone elevated to approximately fivefold above normal, have been observed reproducibly across small and large animal models of PAH (Aguero et al., 2014; Maron et al., 2012). In one cross‐sectional study, peripheral plasma aldosterone was increased significantly in idiopathic PAH (iPAH) compared with control (248.5 ± 38.8 vs. 71.9 ± 18.2 pg·ml⁻¹; P < .05), and high levels of aldosterone were more marked in patients with New York Heart Association (NYHA) Functional Class (FC) II or III status compared to FC I or control (Calvier et al., 2016). In a separate study, pulmonary arterial aldosterone in PAH correlated positively with PVR (r = .72, P < .02) and transpulmonary gradient (r = .69, P < .02) but inversely with cardiac output (r = −.79, P < .005; Maron et al., 2013). These findings suggest that high levels of aldosterone in this population were mediated by release of adrenal aldosterone in the setting of right ventricular(RV) dysfunction, akin to other clinical disorders in which diminished efferent renal arteriolar blood flow stimulates juxtaglomerular release of renin despite normal left ventricular function (Anand et al., 1991). However, data from studies sampling adrenal release of aldosterone directly are lacking, and thus, the pathophysiological basis for high levels of aldosterone in PAH remains incompletely characterized.

To this end, alternative mechanisms to explain high levels of aldosterone in PAH have also been proposed, which could provide important insights into observations suggesting that RAAS‐modulating therapies may be effective despite normal or near normal cardiac output (Hemnes et al., 2018). Indeed, extra‐adrenal synthesis of aldosterone has been reported (Takeda et al., 1996). This may occur in PAH through different mechanisms. For example, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=989 stimulates binding of the steroidogenic transcription factors https://www.guidetopharmacology.org/GRAC/CoregulatorDisplayForward?coregId=62 and steroidogenesis factor‐1 to https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1360 (aldosterone synthase), which converts https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2871 to the aldosterone precursor https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2869. Similarly, hypoxia has been shown to stimulate c‐Fos/c‐Jun binding to the AP‐1 site of StAR, which encodes steroidogenic acute regulatory protein (StAR) that catalyses the first and rate‐limiting step in steroidogenesis (e.g., transport of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2718 from the inner to outer mitochondrial membrane; Maron et al., 2014).

The functional significance of extra‐adrenal aldosterone synthesis in pulmonary artery endothelial cells (PAECs) is not clear, although hypoxia‐induced up‐regulation of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8927 and collagen III is inhibited by https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=626 antagonism with https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2875 or https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2876 (Maron et al., 2014). The pathogenic effects of high levels of aldosterone in PAH more broadly, however, have been well characterized. Activation of https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3004 in PAECs induces vascular ROS accumulation, particularly H₂O₂, that targets critical redox sensitive cysteinyl thiol(s) controlling endothelin https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=220‐dependent https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509 synthesis and NEDD9‐dependent COL3A1 transcription (Maron et al., 2012). Specifically, post‐translational oxidative modification of ET_B‐Cys⁴⁰⁵ and NEDD9‐Cys¹⁸ promotes cell proliferation and fibrillar collagen deposition, as well as paracrine signalling that induces adverse remodelling effects in heterologous vascular cell types, such as pulmonary artery smooth muscle cells (PASMCs). Pharmacological inhibition of the MR, in turn, limits hypertrophic and fibrotic vascular remodelling and improves pulmonary hypertension by attenuating oxidant stress, preventing PDGF‐mediated nuclear translocation of the MR (where it is transcriptionally active; Preston et al., 2013), inhibiting mTORC1 (Aghamohammadzadeh et al., 2016), promoting degradation of the pro‐inflammatory mediator xeroderma pigmentosum group B complementing protein (XPB; Elinoff et al., 2018), or affecting other key intermediaries known to promote PAH, to improve pulmonary hypertension in vivo (Tang et al., 2018). The salutary effect of MR inhibition is not limited to the pulmonary vasculature, as several groups have reported improvement in RV systolic function and morphology, including decreased cardiomyocyte hypertrophy and fibrosis, by MR antagonism (Boehm et al., 2018). It is not clear, however, if this is due to decreased RV afterload, differential drug targeting to the RV, or a combination of both.

The extent to which aldosterone or the MR are modifiable treatment targets, clinically remains an area of active investigation. In one study, gene variants regulating aldosterone metabolism informed treatment response to https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1915 (Halliday et al., 2018), implying hormonal regulation of drug efficacy in PAH. A retrospective analysis of the ARIES‐1 and ARIES‐2 trials suggested that patients randomized to the ET receptor antagonist, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3951 (10 mg daily) and, at the same time, prescribed an MR antagonist, performed significantly better on 6‐min walk distance and had a greater improvement in NYHA FC status, compared with those receiving ambrisentan alone (Maron, Waxman, et al., 2013). These findings raised the possibility that inhibiting ET_A receptor‐dependent vasoconstriction and aldosterone‐induced ET_B receptor dysfunction could be beneficial clinically. Overall, however, data from sufficiently powered PAH clinical trials addressing the utility of MR antagonism in practice remain to be generated.

2.2. Angiotensin II, vascular remodelling, and PAH

An important early observation linking angiotensin II per se to PAH was from Morrell and colleagues, who used in situ hybridization to show increased transcriptional regulation of ACE in muscularized pulmonary arterioles from hypoxia‐treated rats (Morrell, Atochina, Morris, Danilov, & Stenmark, 1995). This was supported further by the same group in experiments demonstrating that compared to control, treatment with the ACE inhibitor, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5158, or the selective https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=34&familyId=6&familyType=GPCR antagonist, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=590, for 14 days improved mean pulmonary artery pressure and attenuated right ventricular hypertrophy significantly (Morrell, Morris, & Stenmark, 1995).

Plasma renin activity and levels of angiotensin I and angiotensin II are increased in patients with severe PAH and are associated with a threefold increased risk for mortality or lung transplantation (HR = 3.02, 95% CI [1.40, 6.48], P = .005; de Man, Tu, et al., 2012). Parallel findings are reported in patients with chronic thromboembolic pulmonary hypertension (CTEPH), and in CTEPH‐PAECs, angiotensin II promotes vascular smooth cell migration by angiotensin AT₁ receptor‐dependent phosphorylation of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=514 (Zhang et al., 2018). Similarly, infusion of angiotensin II in rats induces adventitial fibrosis of the pulmonary artery via increased AT₁ receptor activity (Sun, Ramires, & Weber, 1997). In one study using the pulmonary artery banding model, RV fibrosis associated with losartan‐sensitive increases in key pro‐fibrotic mediators, including https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5060, CTGF, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4470 and ET‐1 (Friedberg et al., 2013). As the determinant of RV afterload in that study was fixed, these results imply that the pro‐fibrotic effects of angiotensin II in PAH may target the RV itself.

Counter‐regulation of classical renin‐angiotensin signalling occurs by two parallel and irreversible pathways. First, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1614 cleaves angiotensin I to angiotensin‐(1‐9). Second, ACE2 may also cleave angiotensin II to yield https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=582 and Ang‐(1‐5) (Maron & Leopold, 2015). The Ang‐(1‐7) peptide activates https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=150, which is an oncogene and a GPCR. Stimulation of Mas by Ang‐(1‐7), in turn, inhibits AT₁ receptor signalling, vascular proliferation, and mitogenic pathways. Leveraging the cardiovascular protective effects of the ACE2‐Mas pathway may have particular relevance in PAH. First, ACE2 is expressed in PAECs, PASMCs, and RV myocardium (Johnson, West, Maynard, & Hemnes, 2011). In experimental PAH, ACE2 expression is increased, but its bioactivity is offset by competing, pleiotropic, and pathogenic signalling pathways characteristic of the disease. Nonetheless, the possibility that ACE2 augmentation could be effective in PAH clinically is supported by a number of basic, translational, and preclinical findings.

Activation of the ACE2/Ang‐(1‐7)/Mas receptor pathway restores the cellular redox balance by inhibiting NOX‐dependent H₂O₂ synthesis. This is associated with an increase in bioavailable NO· and improved NO·‐dependent vascular relaxation and, along with direct suppression of TGF‐β, may account for the protective effect of Ang‐(1‐7) infusion on pulmonary arterial and RV remodelling shown in bleomycin‐treated and monocrotaline‐PAH rodents (Shenoy et al., 2010). ACE2 is also linked to https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2048‐https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2994 inhibition, which, in turn, appears to prevent cell proliferation and migration (Zhong et al., 2010). Within the RV, ACE2/Ang‐(1‐7) enhances cardiomyocyte calcium handling and expression of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=159#841, and dysregulation of SERCA2a has emerged recently in converging lines of research as a bona fide pathobiological mechanism underpinning pulmonary vascular remodelling and RV systolic heart failure in PAH (Hadri et al., 2013).

There is emerging evidence that this pathway may be potentially targeted in PAH. Measurement of ACE2 is challenging due to its very short half‐life; however, the ratio of AngII/Ang‐(1‐7) may be used as a surrogate of ACE2 activity. Patients with PAH have raised AngII/(Ang‐(1‐7) ratios, suggesting reduced ACE2 activity (Hemnes et al., 2018). Augmentation of ACE2 using a recombinant peptide (GSK2586881) was well tolerated in a small pilot study and, in the short term, reduced pulmonary vascular resistance (Hemnes et al., 2018). There is an ongoing international trial of this therapeutic agent but its results are not yet available (NCT03177603 at http://clinicaltrials.gov).

3. NEUROHORMONAL ACTIVATION IN PULMONARY HYPERTENSION: THE AUTONOMIC NERVOUS SYSTEM

Components of the sympathetic branch of the autonomic nervous system implicated in the pathogenesis of PAH include the endocrine and paracrine hormones https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=509, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=484, and https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=940. More recently, the role of parasympathetic nervous system dysregulation on RV cardiac function, particularly via modulation of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=76 (nAChRs), has also been described in PAH. The collective mechanistic importance of catecholamine hormones and the parasympathetic system to pulmonary vascular disease is discussed in greater detail below.

3.1. The sympathetic and parasympathetic nervous systems in PAH

The deleterious effects of adrenergic stimulation on cardiovascular performance in patients with left ventricular systolic heart failure are well recognized (Maron & Leopold, 2010). Early observations of the failing RV in patients with PAH similarly demonstrated abnormalities in adrenergic signalling with evidence of decreased https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=28 density and aberrant activity of the catalytic subunit of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=257#1285 (Bristow et al., 1992). These observations led to investigations focusing on the relationship between the sympathetic signalling and pulmonary vascular disease, which revealed that the adrenoceptors https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=4, β₁, and https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2994, are expressed in pulmonary vascular cell types at densities similar to resistance blood vessels (Rudner et al., 1999). Study of isolated healthy RV cardiomyocytes further revealed that they express the inotropic β₁‐ and β₂‐adrenoceptors, as well as the dopamine receptors https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=220‐ and https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=23. Taken together, these fundamental observations emphasize the potential importance of RV‐pulmonary vascular regulation by neurohumoral mechanisms. Despite this body of evidence, the concept of sympathetic modulation of PAH was not considered as a therapeutic intervention for many years, because of concerns for potential adverse and off‐target effects on the systemic circulation.

In one study involving 60 PAH patients, venous noradrenaline concentration was increased approximately threefold in patients with NYHA functional class III/IV as compared to those with functional class I/II. Noradrenaline levels were also shown to be inversely correlated with cardiac output (Nagaya et al., 2000). Directionally similar findings have been reported in other studies, and muscle‐directed sympathetic nerve activity and heart rate are increased while heart rate variability is decreased in PAH (Nootens et al., 1995; Velez‐Roa et al., 2004). Elevated circulating levels of catecholamines, however, have not translated consistently to increased cardiopulmonary tissue levels or activity of catecholamines (Nootens et al., 1995). In fact, in patients with PAH, tissue levels of noradrenaline were depleted, and AC activation of adenylyl cyclase in response to forskolin was diminished in the failing RV. Moreover, this finding was more pronounced in the failing RV from PAH patients as compared to patients with idiopathic dilated cardiomyopathy (Bristow et al., 1992). Similarly, RV uptake of [¹²³I]metaiodobenzylguanidine, an analogue of noradrenaline, was diminished in patients with PAH and correlated inversely with pulmonary artery pressure (Morimitsu et al., 1996).

Impairment of the parasympathetic nervous system has also been implicated in PAH. Patients with PAH and an RV ejection fraction <41% exhibited decreased heart rate recovery, a surrogate marker of parasympathetic activity, following cardiopulmonary exercise testing than patients with higher RV function (da Silva Goncalves Bos et al., 2018). In lungs and RV tissues explanted from patients with PAH undergoing lung or heart‐lung transplantation, there was increased expression of https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=468 and decreased anticholinesterase activity in the RV. Parasympathetic stimulation was also found to improve experimental pulmonary hypertension. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=8994, which inhibits https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2471 activity to stimulate the parasympathetic nervous system, improved survival, RV, and pulmonary vascular structural and functional remodelling in the Sugen/hypoxia model of pulmonary hypertension (da Silva Goncalves Bos et al., 2018).

At a molecular level, activation of sympathetic signalling leads to stimulation of pathways that promote RV and pulmonary vascular dysfunction and compensatory remodelling. Stimulation of β‐adrenoceptors promotes Gα _S coupling to activate AC‐cAMP‐PKA transduction and synthesis of the vasodilator NO as well as activation of L‐type calcium channels and https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=125, phosphorylation of I‐1, and phospholamban that mediates Na⁺/K⁺‐ATPase pump activity (Maron & Leopold, 2015). Activation of the https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1466 leads to desensitization of β₁‐adrenoceptor signalling in RV cardiomyocytes (Piao et al., 2012). The net effect of activation of this pathway in pulmonary vascular and RV cells is vasodilation and increased cardiac contractility, respectively. Conversely, stimulation of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=4 promotes Gα _q subunit coupling and inhibition of intracellular inorganic calcium (Ca²⁺ _i) release and inhibition of ATP. Imbalance in these pathways favours increased oxidant stress, up‐regulation of the fibrogenic mediators TGF‐β and CTGF, as well as abnormal calcium handling. Together, these molecular changes lead to PAEC dysfunction, PASMC proliferation, cardiomyocyte hypertrophy, and adverse cardiovascular remodelling (Maron & Leopold, 2015).

3.2. The sympathetic nervous system as a therapeutic target

Preclinical studies have demonstrated efficacy of pharmacological inhibition of the sympathetic nervous system in PAH models. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=551, a nonselective α‐ and β‐receptor antagonist with antioxidant properties, improved RV failure and remodelling in the MCT and Sugen/hypoxia rats (Bogaard et al., 2010; Okumura et al., 2015). This was associated with down‐regulation of cardiac hypertrophic, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=625, and ceramide signalling (Drake et al., 2013). Treatment with https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7129 a cardioselective β‐adrenoceptor antagonist, similarly improved RV function while decreasing RV inflammation, fibrosis, and stiffness by increasing phosphorylation of troponin I and myosin binding protein C (de Man, Handoko, et al., 2012). https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7246, a β₁‐adrenoceptor antagonist and a β_2,3‐adrenoceptor agonist, also improved pulmonary artery and RV pressures in the monocrotaline model of PH. Mechanistic in vitro studies revealed that nebivolol decreased endothelial proliferation and production of pro‐inflammatory cytokine https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4998, the chemokine https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=771, and the vasoconstrictor ET‐1 (Perros et al., 2015).

Despite substantial evidence of activation of the sympathetic nervous system in PAH, pharmacological interruption of this pathway using β‐adrenoceptor antagonists (β‐blockers) is currently not recommended. Early observational studies performed using older generation β‐blockers at high doses reported no difference in exercise tolerance between treated and untreated patients or significant functional improvement after withdrawal of β‐blockers. More recently, with mounting evidence from preclinical studies that next generation β‐blockers improve cardiopulmonary function in pulmonary hypertension, investigators have started to trial these agents in patients. A double‐blind, randomized, controlled trial with carvedilol performed at a single centre demonstrated that carvedilol was safe and well tolerated with no decrement in exercise capacity, RV function, or cardiac output (Farha et al., 2017). In contrast, in a crossover study of bisoprolol, while there was a trend towards increased RV ejection fraction, cardiac index and 6‐MWD were decreased, leading investigators to conclude that bisoprolol offered no therapeutic benefit in PAH (van Campen et al., 2016). Thus, while early randomized studies show no harm from next generation β‐blockers in patients with PAH, further large‐scale randomized controlled trials are warranted before they are used widely in this patient population.

The therapeutic potential of interventional inhibition or disruption of the sympathetic nervous system in PAH has been investigated in preclinical models and patients. Sympathetic ganglion block accomplished by injection of https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7602 into the left superior cervical ganglion resulted in a decrease in cardiopulmonary pressures and pulmonary arteriole remodelling (Perros et al., 2015). Pulmonary artery denervation, which ablates sympathetic nerves in the pulmonary vasculature at the bifurcation of the main pulmonary artery and the ostium of the right and left pulmonary arteries, has been evaluated as a therapy for PAH. As pathological examination of human pulmonary arteries revealed that they are innervated predominantly by sympathetic nerves with the majority of nerves at a depth of <4 mm, denervation using a catheter‐based intervention is a rational therapy (Rothman et al., 2019). The first‐in‐patient study reported procedural success (decrease in PA pressure of ≥10 mmHg) in 12 of 13 recipients with improved World Health Organization class and Borg score (Chen et al., 2013). In a second study of 66 patients that underwent denervation, at 1‐year follow‐up, 6‐min walk distance increased by an average of 94 m, with a low rate of adverse events (Chen et al., 2015). Although these results are promising, a randomized sham‐controlled trial akin to the study design of the Renal Denervation in Patients with Uncontrolled Hypertension (SYMPICITY HTN‐3) trial is warranted before pulmonary artery denervation becomes a mainstream therapy (Bhatt et al., 2014).

4. METABOLIC SYNDROME

Metabolic syndrome is defined as enlarged waist circumference, elevated triglycerides, reduced HDL cholesterol, elevated systemic BP, and elevated fasting glucose (Alberti et al., 2009). While the systemic vascular consequences of these conditions have been extensively studied, the pulmonary vascular consequences are less known. Initial reports from Zamanian et al. (2009) demonstrated elevated prevalence of https://www.guidetopharmacology.org/GRAC/DiseaseDisplayForward?diseaseId=280 in PAH compared with the National Health And Nutrition Examination Survey (NHANES) cohort, and since then, there have been numerous clinical and preclinical studies to understand this association and to attempt to correct insulin resistance and other metabolic disease in PAH. The emerging picture is that dysregulated metabolism, particularly in the insulin pathway, is a feature of PAH and that there may be a role for its reversal in therapy of PAH.

4.1. Preclinical studies

A key early observation that metabolic dysfunction may play a role in the development of pulmonary vascular disease was that in endothelial cells isolated from patients with iPAH, there was increased oxygen consumption coupled with a decrease in NO synthesis (Xu et al., 2007). These iPAH endothelial cells further had a greater reliance on cellular respiration for energy production and threefold higher glycolytic rate than controls. Alterations in mitochondrial structure and function may underlie many of these metabolic changes (Archer et al., 2008; Archer, Fang, Ryan, & Piao, 2013) and are likely affected by the metabolic pathways described below. Additionally, several cell types are now known to display glycolysis in PAH including smooth muscle cells (Goncharov et al., 2014), fibroblasts (Li et al., 2016), platelets (Nguyen et al., 2017), and circulating immune cells (Stenmark, Tuder & El Kasmi, 2015). These data point to a globally disorganized metabolism in PAH.

Mutations in the https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1794 gene (BMPR2) underlie most cases of heritable PAH, and reduced expression or actual mutation of BMPR2 has been described to be highly prevalent in other more common forms of PAH, such as iPAH (Richter et al., 2004; Thomson et al., 2000). A member of the TGF‐β family, BMPR2 modulates tissue injury, repair and many other signalling mechanisms including cytoskeletal function (West, 2010). Rodent models of BMPR2 mutation and suppression thus provide unique opportunities to study molecular mechanisms of PAH.

Following the original observation that insulin resistance is highly prevalent in PAH, Rabinovitch and colleagues demonstrated that the metabolic transcription factor, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=595 is a downstream target of BMPR2 (Hansmann et al., 2008). PPARγ plays a key role in glucose and lipid homeostasis. Not surprisingly, in the context of BMPR2 mutation, PPARγ is suppressed, leading to transcription of growth‐promoting genes including ApoE. In rodent models, PPARγ agonists could rescue the normal BMPR2 downstream signalling phenotype and in an ApoE knockout rodent model, high fat diet promoted PAH (Hansmann et al., 2007). These early data have provided key evidence that BMPR2 suppression and/or mutation may drive metabolic dysfunction and could be a target for intervention, even in the context of mutation.

In a different line of evidence, we have used a transgenic rodent model of mutant BMPR2 overexpression (BMPR2^R899X) to demonstrate that insulin resistance occurs before development of pulmonary vascular disease in this model. It was noted that this rodent line developed obesity shortly after the transgene was induced at approximately 6–8 weeks of age and well before the onset of PAH, approximately 6 weeks later (Johnson et al., 2012). Insulin resistance is demonstrable just 2 weeks after transgene induction, thus suggesting a potential causal role for insulin resistance in PAH development (West et al., 2013). Moreover, when fed a high fat diet, a well‐known model of insulin resistance in rodents, the BMPR2^R899X develops more severe PAH than those fed a standard diet. Further, even rodents without BMPR2 mutation develop mild elevations in pulmonary arterial pressure. In both the BMPR2^R899X mice and wild type controls, pulmonary arterial pressure was directly correlated with plasma insulin levels but not plasma glucose levels (Trammell et al., 2017). These data provide further evidence of a causal relationship between insulin resistance and PAH development.

Of note, in mice, genetic knockout of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=848#2709, a sirtuin mitochondrial protein that regulates metabolism by functioning as a deacetylase, results in spontaneous PAH (Paulin et al., 2014). SIRT3 protein expression is reduced in both rodent models of PAH and also human PAH tissue. And, additionally, a SIRT3 loss of function polymorphism was associated with idiopathic PAH in humans, thus demonstrating that there may be other genetic regulators of metabolism playing important roles in PAH development.

As described above, metabolic syndrome includes several other features beyond insulin resistance alone, particularly obesity and dyslipidaemia. Adipokines, cytokines secreted by adipose tissue, have been implicated in PAH as well. In Hansmann's work on the BMPR2/PPARγ axis, the ApoE knockout mouse fed high fat diet developed PAH inversely proportional to https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3726 levels (Hansmann et al., 2008). Adiponectin knockout mice also develop PAH in an age‐dependent manner (Summer et al., 2009), and Medoff and colleagues have demonstrated that adiponectin deficiency results in airway remodelling as well as pulmonary vascular remodelling (Medoff et al., 2009; Weng et al., 2011). https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5015 is another traditional adipokine that can be synthesized by endothelial cells. Huertas et al. have demonstrated enhanced leptin secretion by IPAH endothelial cells, compared with controls and further demonstrated that https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=307#1712 is enhanced on pulmonary arterial smooth muscle cells (Huertas et al., 2012, 2015). They further demonstrated that leptin receptor‐deficient rats develop less severe PH when exposed to hypoxia, suggesting a potential causative role for this receptor in PAH. These data suggest that in addition to insulin resistance, obesity and associated adipokines may be features of the metabolic syndrome that promote PAH.

While there is emerging human data that dyslipidaemia is common in PAH, mechanistic rodent and cell culture data are less well defined. Oxidation of LDL through various reactions involving transition metals and ROS generates oxidized LDL (oxLDL), which, in turn, is known to play a key role in systemic vascular disease. Interestingly, overexpression of the oxLDL receptor, LOX‐1, on lung endothelial cells promotes oxidant stress and can worsen chronic hypoxic PH (Sharma et al., 2016).

Development of RV failure in PAH is a strong determinant of mortality, and the RV is highly metabolically active. While the pulmonary vasculature is the main focus of many studies, there is increasing evidence that the right ventricle is similarly affected by metabolic disease. Cardiomyocytes primarily prefer fatty acid oxidation for energy production (Lopaschuk, Ussher, Folmes, Jaswal, & Stanley, 2010) Rodent and cell culture data have shown increased glucose metabolism in the RV (Archer, Fang, Ryan, & Piao, 2013; Piao, Fang, Cadete, Wietholt, Urboniene, Toth, et al., 2010; Piao et al., 2013; Piao, Marsboom, & Archer, 2010); there is also evidence of altered lipid metabolism with increased lipid import into the failing RV cardiomyocytes and reduced fatty acid oxidation (Brittain et al., 2016; Graham et al., 2015; Hemnes et al., 2014; Talati et al., 2016). These data suggest that in addition to pulmonary vascular disease, metabolic dysfunction may play a role in RV failure as well.

4.2. Translational studies

Strengthening the impact of the basic science data, there are strong clinical studies showing that metabolic dysfunction is present in human PAH. Most work thus far has focused on insulin resistance. Insulin is a peptide hormone that regulates glucose and lipid homeostasis, and thus, insulin resistance can be defined in both the glucose and lipid axes. In an early observation, Xu et al. (2007) noted increased glucose uptake in the lungs of PAH patients measured by Fludeoxyglucose ([¹⁸F]DG) uptake at PET. Later, Zamanian built on these data with a description of insulin resistance in PAH in which insulin resistance was defined by the triglyceride : HDL (TG : HDL) ratio. When TG : HDL is elevated, insulin resistance is present and, indeed, that ratio was more likely to be elevated in PAH patients than in matched controls from the NHANES database (Zamanian et al., 2009). Pugh et al. (2011) extended these results by studying glycosylated haemoglobin in PAH patients and found that this key marker of elevated plasma glucose was present in about half of PAH patients without known diabetes and was not correlated with body mass index (BMI), suggesting that obesity alone could not account for the elevation in glycosylated haemoglobin. Heresi et al. (2017) performed oral glucose tolerance testing on PAH patients and found, surprisingly, reduced insulin secretion compared to matched controls and increased energy expenditure. Based on this paradox of evidence of insulin resistance yet reduced insulin secretion, our group have performed comprehensive metabolic studies in PAH patients incorporating detailed plasma metabolomic profiles and lipoprotein analyses as well as oral glucose tolerance testing. We found that insulin resistance as defined by the glucose axis (e.g., glycosylated haemoglobin and HOMA‐IR) was not more common in PAH than age‐, sex‐, and BMI‐matched controls. However, when the lipid axis of insulin resistance was studied, PAH patients were significantly more likely to be insulin resistant, and these lipid features of insulin resistance were more associated with an inflammatory markers, linking insulin resistance with inflammatory markers previously associated with PAH (Hemnes et al., 2019; Price et al., 2012). Similar to earlier animal work on oxLDL (Sharma et al., 2016), we found that plexiform lesions of PAH patients had increased oxLDL immunostaining and that it appeared to co‐localize to macrophages. These data have collectively shown that insulin resistance is not due to enhanced secretion of insulin by the pancreas in PAH and is manifested most clearly as altered lipid metabolism, which may promote inflammation perhaps through oxidized LDL‐mediated vascular injury.

As insulin resistance, glucose homeostasis, and dyslipidaemia are closely linked in human PAH, we have not considered each separately. However, with regard to studies of adipokines in PAH, the strongest data are in those concerning leptin. In addition to the preclinical and histological data mentioned above, leptin has been studied in human PAH. Tonelli and colleagues demonstrated that in (Tonelli, Aytekin, Feldstein, & Dweik, 2012) PAH patients, leptin levels were directly associated with BMI and that lower leptin levels were associated with increased mortality. Further studies of adipokines in human PAH patients would enhance the understanding of how these potent hormones may mediate pulmonary vascular disease.

In addition to the above studies related to general metabolism in PAH, there is growing data that the RV in living humans with PAH have altered metabolism. In addition to increased glucose uptake measured by [¹⁸F]DG PET (Bokhari et al., 2011), Brittain has also demonstrated increased RV lipid content consistent with lipotoxicity in living humans with PAH (Brittain et al., 2016), confirming the previously mentioned animal studies (Brittain et al., 2016; Graham et al., 2015; Hemnes et al., 2014; Talati et al., 2016).

4.3. Metabolic interventional studies

If metabolic dysfunction can promote PAH, the question arises whether reversal of metabolic disease can improve or treat PAH. Early evidence that this might be an effective strategy comes from bariatric surgery. Case reports have suggested improvement in PAH with bariatric surgery, as shown by reversal of metabolic syndrome (Mathier, Zhang, & Ramanathan, 2008; Pugh et al., 2013). While this intervention is certainly too risky to be recommended as a therapy for PAH per se, it does suggest that metabolic interventions are worth studying in PAH. Given the availability of safe and well‐tolerated metabolism‐modulating therapies, there has been interest in drug repurposing and study of these therapies in PAH.

One feature of the metabolic dysfunction of PAH is suppression of mitochondrial glucose oxidation and enhanced glycolysis that may drive a pro‐proliferative phenotype of pulmonary vascular cells. Building on rodent work showing up‐regulation of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=596 an inhibitor of mitochondrial pyruvate dehydrogenase, which is a key entry point for pyruvate into the TCA cycle, in PAH (Michelakis et al., 2002; Sutendra & Michelakis, 2014), Michelakis and colleagues performed a pilot study of an inhibitor of PDK, dicholoroacetate (https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4518), in PAH patients (Michelakis et al., 2017). They found that DCA in low to moderate doses was well tolerated and, in a portion of patients, improved pulmonary vascular haemodynamics. They identified gene polymorphisms in mitochondrial metabolism that predicted drug responses as well. How this information can be used in the clinic is presently not clear but it does suggest that metabolic intervention is likely to be safe and possibly effective in PAH.

Other drugs are presently under study for PAH and RV dysfunction in PAH including https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4503, an anti‐diabetic agent (NCT01884051), https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7291 (NCT02829034, NCT01839110, and NCT02133352), and trimetazidine (NCT03273387) that reduce fatty acid metabolism. Presently, it is not known whether further inhibition of fatty acid oxidation may improve or worsen RV function in PAH. Metformin, which has multiple effects including improved insulin sensitivity, enhanced fatty acid oxidation, and reduced hepatic gluconeogenesis, improved RV function in rodent models (Talati et al., 2016). In this context, metformin is likely to exert its effects in PAH through enhanced fatty acid oxidation, although there is data demonstrating that metformin limits pressure overload induced cardiac hypertrophy via activation of https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=474, a serine–threonine kinase energy sensor (Gundewar et al., 2009; Sasaki et al., 2009; Zhou et al., 2001). Thus, there are many potential areas in which this therapy could be beneficial. Finally, it is not known if currently FDA‐approved PAH therapies alter metabolism in PAH, and this may be one of the many effects of these drugs.

4.4. Non‐group 1 PH

Few mechanistic data are available on metabolic syndrome as a direct mediator of pulmonary vascular remodelling in non‐group 1 PH. For example, the contribution of metabolic syndrome to CTEPH or PH associated with lung disease, with the exception of obstructive sleep apnoea or obesity hypoventilation, is not known. However, it seems likely that group 2 PH, pulmonary venous hypertension, is affected by metabolic dysfunction. Emerging preclinical data suggest that metabolic syndrome may promote pulmonary hypertension. First, Meng et al. (2017) demonstrated that certain rodent strains are more susceptible to develop PH when fed a high fat diet to promote heart failure with preserved ejection fraction. Second, there has been further evidence that metformin may have a role in treatment of heart failure with preserved ejection fraction‐associated PH in the context of metabolic disease (Goncharov et al., 2018; Lai, Wang, & Gladwin, 2019). Finally, in a recent manuscript, Ranchoux et al. (2019) demonstrated that the anti‐psychotic https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=47, which is known to cause insulin resistance and metabolic dysfunction, can be used to induce a rodent model of heart failure with preserved ejection fraction‐PH. Further work is needed to fully understand how metabolic syndrome may promote PH in these rodent models and in human disease, where there is very limited information.

5. KNOWLEDGE GAPS AND FUTURE DIRECTIONS

There are a number of important knowledge gaps in both the effects of the neurohormonal milieu on PAH and also the role of metabolism in PAH. For example, the extent to which extra‐adrenal aldosterone synthesis contributes to vascular remodelling in PAH, independent of high levels of aldosterone mediated by classical RAAS overactivation, is not known. Although converging lines of evidence suggest that aldosterone antagonism may be clinically effective, prospective clinical trials on this topic remain to be undertaken. In the field of metabolism and PAH, there are many important remaining questions. On a preclinical level, while there is a robust literature on glucose and fat metabolism in PAH, metabolism in other pathways is little explored, for example, amino acid and nucleic acid metabolism. Additionally, it is still not known exactly how BMPR2 regulates metabolic pathways. Lastly, how and when to best correct metabolic disease in PAH is presently a matter of debate. For instance, enhancement or suppression of fatty acid oxidation have both been proposed as therapies for PAH. It is possible, indeed likely, that the effects of metabolic intervention in the RV may be different from those in the pulmonary vasculature. Thus, any interventional trial will need to examine the effects on both. Recently completed and ongoing trials that target neurohormonal activation or metabolic dysfunction in PAH are outlined in Table 1.

Table 1.

Potential therapeutic options targeting neurohormonal activation or metabolic disease in PAH

Title of study	Intervention	Population	NCT #	Status
RAAS activation interventions
β‐Blockers for the treatment of PAH in children	Carvedilol	PAH, aged 8–17.5 years	NCT017233716	Withdrawn before enrolment
β‐Blockers in i‐PAH	Bisoprolol	PAH, aged 18 and older	NCT01246037	Published—Drug was tolerated but safety concerns were raised (van Campen et al., 2016).
β‐Blockers in pulmonary arterial hypertension	Carvedilol	PAH, aged 18 and older	NCT02507011	Recruiting
Carvedilol PAH a pilot study of efficacy and safety	Carvedilol	PAH, aged 18 and older	NCT02120339	Terminated, not published
PAH treatment with carvedilol for heart failure	Carvedilol	PAH, aged 18 and older	NCT01586156	Published—Drug was tolerated, no decrease in RV function or 6 min walk (Farha et al., 2017)
Pilot study of the safety and efficacy of carvedilol in pulmonary arterial hypertension	Carvedilol	PAH, aged 18 and older	NCT00964678	Published—Carvedilol was tolerated in a pilot study (Grinnan et al., 2014)
Spironolactone for PAH	Spironolactone	PAH, aged 18 and older	NCT01711620	Recruiting
The combination ambrisentan plus spironolactone in pulmonary arterial hypertension study	Spironolactone + ambrisentan	PAH, aged 18 and older	NCT02253394	Terminated—low enrolment
Effects of spironolactone on collagen metabolism in patients with pulmonary arterial hypertension	Spironolactone	PAH, aged 18 and older	NCT01468571	Unknown
Spironolactone combined with captopril and carvedilol for the treatment of pulmonary arterial hypertension	Spironolactone	PAH, aged 18 and older	NCT00240656	Completed, data not published
Modulating effects of lisinopril on sildenafil activity in pulmonary arterial hypertension (MELISSA)	Lisinopril	PAH, aged 18 and older	NCT01181284	Completed, not published. Effects of other captopril can be found here (Alpert, Pressly, Mukerji, Lambert, & Mukerji, 1992; Ikram, Maslowski, Nicholls, Espiner, & Hull, 1982)
Hormonal, metabolic and signalling interactions in PAH	rhACE2	PAH, aged 18 and older	NCT01884051	Published—Acute administration of rhACE2 well tolerated with reduction in PVR (Hemnes et al., 2018)
Metabolic interventions
Evaluation of metformin activity in addition to conventional treatment of grade II or III pulmonary arterial hypertension	Metformin	PAH, aged 18 and older	NCT0135026	Withdrawn, low enrolment
Hormonal, metabolic and signalling interactions in PAH	Metformin	PAH, aged 18 and older	NCT01884051	Completed, not published
Interventions against insulin resistance in pulmonary arterial hypertension	Metformin, exercise	PAH, aged 18 and older	NCT03617458	Enrolling
Ranolazine and pulmonary hypertension	Ranolazine	PAH, aged 18 and older	NCT01174173	Published—Drug was safe, improved symptoms but no change in haemodynamics (Khan et al., 2015)
A study of ranolazine acute administration and short term administration in pulmonary arterial hypertension	Ranolazine	PAH, aged 18 and older	NCT01757808	Published—Drug was safe, but there were no acute haemodynamic effects (Gomberg‐Maitland et al., 2015)
11C‐acetate/18Fluorodeoxyglucose‐FDG PET/CT and cardiac MRI in pulmonary hypertension	Ranolazine	PAH, aged 18 and older	NCT01917136	Completed, not published
Trimetazidine in pulmonary arterial hypertension	Trimetazidine	PAH, aged 18 and older	NCT02102672	Unknown

Abbreviations: PAH, pulmonary arterial hypertension; RV, right ventricle; rhACE2, recombinant human ACE 2. Status is as of December 3, 2019.

Figure 1.

Dysregulated neurohumoral and metabolic signalling promote pulmonary arterial hypertension (PAH). Acquired and genetic risk factors predispose to dysregulated cellular metabolism involving pulmonary artery endothelial cells, pulmonary artery smooth muscle cells, and right ventricular (RV) cardiomyocytes. This induces various intermediate pathophenotypes involved in the progression of PAH (red box). Similarly, chronic elevation in RV afterload in PAH results in cavitary dilation and impaired efficiency, including decreased right ventricular‐pulmonary arterial (RV‐PA) coupling. A decrease in cardiac output up‐regulates the renin‐angiotensin‐aldosterone system (RAAS), which is independently associated with cardiovascular remodelling and PAH progression. Abnormal sympathetic and parasympathetic nervous system (NS) increase pulmonary arterial tone and impair RV diastolic function, respectively, although the precise cellular targets modulating these effects remain incompletely characterized. AFB, adventitial fibroblast; ApoE, apoplipoprotein E; Ang, angiotensin; BPMR2, bone morphogenetic protein receptor‐2; CM, cardiomyocyte; JG, juxtaglomerular; LV, left ventricle; CO, cardiac output; PAEC, pulmonary artery endothelial cell; PDK, pyruvate dehydrogenase kinase; VSMC, vascular smooth muscle cell. The plexiform lesion micrograph was reproduced with permission from J Clin Pathol 2009;62:387–401, and the cardiac MRI image was provided courtesy of Dr. Chuck‐Hou Yee, from Right Ventricle Segmentation From Cardiac MRI: A Collation Study, Medical Image Analysis, vol. 19, pp 187–202, 2015

Figure 2.

Aldosterone and endothelial dysfunction in pulmonary arterial hypertension (PAH). In PAH, increased circulating aldosterone (ALDO) may be due to stimulation of adrenal zona glomerulosa (ZG) cells by endothelin‐1 (ET‐1) or as a result of decreased cardiac output (CO). High levels of ALDO stimulate the mineralocorticoid receptor (MR) to activate NOX4 thereby generating hydrogen peroxide (H₂O₂) in addition to other free oxygen radicals to perturb the redox balance of pulmonary artery endothelial cells (PAECs). Increased ROS accumulation oxidatively modifies functionally essential protein cysteinyl thiols in the eNOS activating region of the endothelin ET_B receptor to decrease bioavailable NO (NO•). ALDO‐induced oxidant stress also modified the Cass protein NEDD9 at Cys¹⁸, which prevents NEDD9‐SMAD3 complex formation that induces NEDD9‐dependent up‐regulation of COL3A and collagen III. Alternative mechanisms associated with extra‐adrenal ALDO synthesis in PAECs have also been proposed, including hypoxia‐mediated up‐regulation of steroidogenic acute regulatory protein (StAR). Overall, high levels of ALDO promote endothelial fibrosis as well as collagen deposition in pulmonary artery smooth muscle cells (PASMCs) through paracrine signalling involving exosomes. Pharmacological antagonism of the MR with spironolactone (SPIRO) or eplerenone (EPL) inhibits ALDO‐induced vascular fibrosis and pulmonary hypertension in experimental PAH. NOX4; SOxH, higher oxidative species of cysteine; SO₃H, sulfonic acid; eNOS, endothelial NO synthase; N9, NEDD9; CTGF, connective tissue growth factor; NKx2‐5, NK2 homeobox 5. The ET_B receptor crystal structure was accessed from DOI https://doi.org/10.2210/pdb6K1Q/pdb

Figure 3.

Adrenoceptor signalling, intracellular calcium, and pulmonary artery smooth muscle cell proliferation. In pulmonary artery smooth muscle cells (PASMC), β‐adrenoceptors (AR) activate AC to increase cAMP and, thereby, activate PKA. PKA phosphorylates phospholamban (PLN) and increase activity of the sarcoplasmic reticulum Ca²⁺‐ATPase (SERCA2), which decreases intracellular Ca²⁺ levels. In pulmonary hypertension, SERCA2 expression is down‐regulated. This results in high intracellular Ca²⁺ levels through the actions of the ryanodine receptors (RYR) and α‐adrenoceptor (AR) signalling. The elevated levels of intracellular Ca²⁺ stimulate proliferation through protein phosphatase 2B (PP2B), translocation of nuclear factor of activated T cells (NFAT) to the nucleus to promote transcription of cyclin D1. PLC, phospholipase C; IP₃, inositol trisphosphate. Reproduced with permission from Circulation. Maron and Leopold (2015)

6. CONCLUSIONS

Taken together, the data on neurohormonal activation and metabolic disease in PAH provide convincing evidence that PAH, while primarily characterized by pulmonary vascular pathology, is markedly affected by the hormonal milieu of the whole body. In this system, perturbations in the pulmonary vasculature can be affected by the RAAS, the sympathetic nervous system, as well as metabolic signalling pathways. The translation of preclinical data to human patients is already beginning to shed light on how interventions in these pathways affect pulmonary vascular disease and right heart function in PAH, in particular. These pathways are little studied in non‐group 1 PH and that may be an important area of future research. In the meanwhile, the availability of more specific interventions on neurohormonal or metabolic signalling alterations may ultimately lead to more effective therapies of this deadly disease.

6.1. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Christopoulos et al., 2019; Alexander, Cidlowski, et al., 2019; Alexander, Fabbro et al., 2019; Alexander, Kelly et al., 2019; Alexander, Mathie, et al., 2019).

ACKNOWLEDGEMENTS

This study was funded by National Heart, Lung, and Blood Institute (U01125215) and American Heart Association (19AIML34980000) (J.A.L). National Scleroderma Foundation (R56HL131787, R01HL139613‐01, and R21HL145420) and Cardiovascular Medical Research Education Foundation (B.A.M.). National Heart, Lung, and Blood Institute (1RO1HL142720, 6R01HL122417, 5U01HL125212, and P01HL108800) (A.R.H.).

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

Maron BA, Leopold JA, Hemnes AR. Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension. Br J Pharmacol. 2020;177:1457–1471. 10.1111/bph.14968