Emerging therapeutics in pulmonary hypertension.

Hensley MK; Levine A; Gladwin MT; Lai YC

doi:10.1152/ajplung.00259.2017

Emerging therapeutics in pulmonary hypertension.

Affiliations

1. Division of Pulmonary and Critical Care Medicine, University of Michigan , Ann Arbor, Michigan.
Authors
Hensley MK¹
(1 author)
2. Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania.
Authors
Levine A²
Gladwin MT²
Lai YC²
(3 authors)

American Journal of physiology. Lung Cellular and Molecular Physiology, 01 Feb 2018, 314(5):L769-L781
https://doi.org/10.1152/ajplung.00259.2017 PMID: 29388467 PMCID: PMC6008125

ReviewFree full text in Europe PMC

Abstract

Pulmonary hypertension (PH) is a progressive and often fatal illness presenting with nonspecific symptoms of dyspnea, lower extremity edema, and exercise intolerance. Pathologically, endothelial dysfunction leads to abnormal intimal and smooth muscle proliferation along with reduced apoptosis, resulting in increased pulmonary vascular resistance and elevated pulmonary pressures. PH is subdivided into five World Health Organization groups based on the disease pathology and specific cause. While there are Food and Drug Administration-approved medications for the treatment of pulmonary arterial hypertension (PAH; Group 1 PH), as well as for chronic thromboembolic PH (Group 4 PH), the morbidity and mortality remain high. Moreover, there are no approved therapies for other forms of PH (Groups 2, 3, and 5) at present. New research has identified molecular targets that mediate vasodilation, anti-inflammatory, and antifibrotic changes within the pulmonary vasculature. Given that PAH is the most commonly studied form of PH worldwide and because recent studies have led to better mechanistic understanding of this devastating disease, in this review we attempt to provide an updated overview of new therapeutic approaches under investigation for the treatment of PH, with a particular focus on PAH, as well as to offer guidelines for future investigations.

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Am J Physiol Lung Cell Mol Physiol. 2018 May 1; 314(5): L769–L781.

Published online 2018 Feb 1. https://doi.org/10.1152/ajplung.00259.2017

PMCID: PMC6008125

PMID: 29388467

Emerging therapeutics in pulmonary hypertension

Matthew K. Hensley,¹ Andrea Levine,^2,³ Mark T. Gladwin,^2,³ and Yen-Chun Lai^2,³

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Abstract

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INTRODUCTION

Pulmonary hypertension (PH) is a progressive illness often presenting with nonspecific symptoms including dyspnea, dizziness, lower extremity edema, and decreased exercise tolerance (58). At the cellular level, it is characterized by endothelial cell dysfunction and increased contractility of the small pulmonary arteries, which lead to abnormal intimal and smooth muscle proliferation together with resistance to apoptosis (108, 122, 128, 129). Pulmonary vascular remodeling is a prominent feature of PH independent of the etiology (17, 58). This remodeling increases pulmonary vascular resistance (PVR), which eventually leads to failure of the right ventricle (RV) due to rising afterload. Many symptoms of PH, including lower extremity edema and dyspnea, arise from RV failure (108, 128, 129).

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DEFINITION OF PH

PH is defined by end-expiratory mean pulmonary artery pressure ≥25 mmHg and PVR >3 Wood units at rest (58, 124). PH is a nonspecific umbrella term, which covers elevated pulmonary artery pressure regardless of the etiology. The initial clinical classification of PH has arisen from a World Health Organization-sponsored international meeting in 1973 (53). In 1998, PH was subdivided into five World Health Organization groups based on the disease pathology and specific cause. Pulmonary arterial hypertension (PAH; Group 1 PH) specifically refers to disease processes, which result in vasoconstriction and stiffening of the small arteries in the lungs secondary to cell proliferation, fibrosis, as well as the development of in situ thrombi or plexiform lesions. This pathology both defines PAH and unifies the multiple etiologies, which may lead to the development of the disease. PAH can be idiopathic, can be heritable, and can be associated with connective tissue disease, HIV, drug use, etc. (see Fig. 1 for the updated clinical classification of PH from the 5th World Symposium held in Nice, France, in 2013) (58, 118). There are other pathologies in which PH presents as a secondary disease, including left heart disease (Group 2), chronic lung diseases and/or hypoxia (Group 3), chronic thromboembolic pulmonary hypertension (CTEPH, Group 4), and miscellaneous or multifactorial etiologies (Group 5).

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Fig. 1.

Clinical classification of pulmonary hypertension (PH) from the 5th World Symposium held in Nice, France, in 2013. [Adapted from Simonneau et al. (118) with permission from the publisher, copyright 2013, Elsevier] BMPR2, bone morphogenetic protein receptor 2; PVR, pulmonary vascular resistance; FDA, Food and Drug Administration; COPD, chronic obstructive pulmonary disease.

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CURRENT THERAPIES FOR PH

Current therapies targeting endothelial function and vasodilation/antiproliferation via three major pathways associated with prostacyclin (PGI₂), nitric oxide (NO), and endothelin-1 (ET-1) have led to the rapid clinical development of >10 major Food and Drug Adminisration (FDA)-approved medications for the treatment of PAH (Fig. 2) (7, 61, 74, 106). In 2013, riociguat, a member of soluble guanylyl cyclase stimulators, has also been approved for the treatment of both PAH and CTEPH (43, 44). Although there are 14 FDA-approved drugs for the treatment of PAH available on the market, class-specific side effects (hypotension and myalgia for phosphodiesterase type-5 inhibitors; significant hypotension with no evident myalgia for soluble guanylate cyclase stimulator; anemia and edema for endothelin receptor antagonists; see Fig. 2 for more details) are commonly reported, and mortality with the current therapies remains high, with the estimated rates of 15, 30, and 45% at 1, 2, and 3 yr from diagnosis, respectively (58). At present, there are no approved therapies for other forms of PH (Groups 2, 3, and 5). Moreover, therapies approved for PAH, such as treatment with sildenafil and tadalafil, have been found to be ineffective or exhibited controversial results in patients with Groups 2 and 3 PH (22, 45, 48, 79, 110). Thus there is an important unmet need in identifying new therapeutic approaches to provide a significant positive impact on disease progression and to improve patient outcomes. Given that PAH is the most commonly studied form of PH worldwide and because recent studies have led to better mechanistic understanding of this devastating disease, the emerging targets and therapies for PAH is the main focus of this review.

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Fig. 2.

Current therapies approved for treatment of pulmonary arterial hypertension (PAH) among prostacyclin, nitric oxide (NO), and endothelin (ET)-1 pathways. sGC, soluble guanylyl cyclase; PDE-5, phosphodiesterase type 5; PPARγ, peroxisome proliferator-activated receptor-γ.

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EMERGING TARGETS AND THERAPIES FOR PAH

Here, we will first focus on drugs that modulate the vasodilator/vasoconstrictor balance, and then, we will review drugs that target the proliferative antiapoptotic behavior of the pulmonary endothelial and smooth muscle cells. New approaches targeting inflammation and disordered metabolism will also be discussed.

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VASODILATORS

Apelin

Apelin is a ligand for the apelin receptor (also known as APJ, APLNR, and AGTRL1), a G protein-coupled receptor predominantly located in the lung, heart, endothelium, kidney, and brain (64, 68). In the lung, apelin is localized exclusively in endothelial cells of small pulmonary arteries and is regulated by hypoxia-inducible factor-1α, as well as bone morphogenetic protein receptor 2 (BMPR2) (68, 69). The apelin-APJ axis modulates vascular tone, apoptosis, NO-dependent vasodilation, and cardiac contractility (68).

There are several downstream effectors of apelin, such as microRNAs (miR) 424/503, which inhibits fibroblast growth factor 2 (2, 68, 69). Reduced expression of miR 424/503, together with the subsequent increased fibroblast growth factor 2 expression, has been shown to induce pulmonary vascular remodeling and vasoconstriction in pulmonary artery endothelial cells (PAECs) from patients with PAH and in monocrotaline (MCT) rat model of PAH (69). In fact, administration of apelin or miR 420/503 has been shown to prevent and rescue preclinical models of PAH (2, 37, 69). Nevertheless, miR 424/503 is not exclusively regulated by apelin. In mammary epithelium, this miR cluster has been shown to be transcriptionally controlled by transforming growth factor-β (TGF-β), where induction of miR 424/503 regulates cell apoptosis and cell cycle arrest through downregulation of CDC25A (86). Apelin has also been reported to regulate the ATPase activity of the endothelial enzyme CD39, which is significantly downregulated in the lungs and PAECs from patients with PAH (54). Moreover, suppression of CD39 is associated with vascular dysfunction and remodeling in lungs and cultured PAECs from patients with PAH (54).

No less important is another pathway in which APJ activates AMPK, Kruppel-like factor 2, and endothelial nitric oxide synthase (eNOS), which enhance NO production and vasodilation. Another newly discovered mediator, Elabela/Toddler, an endogenous agonist of the APJ, has been shown to be downregulated in lungs from PAH patients, as well as in both MCT and Sugen/hypoxia (SuHx) rat models of PAH (136). Administration of Elabela/Toddler attenuates RV systolic pressures, pulmonary vascular remodeling, and RV hypertrophy in rats with PAH-induced by MCT (136). Clinical trials have shown that apelin increases cardiac output and stoke volume in patients with PAH, although no changes in mean pulmonary artery pressure and systemic vascular resistance were observed (16).

Dehydroepiandrosterone

Dehydroepiandrosterone (DHEA) is a cholesterol-derived hormone made in and secreted from the adrenal cortex. It serves as a precursor for estrogens and androgens in the body. Low DHEA levels in men have been associated with PAH (130). DHEA treatment has been shown to prevent and reverse chronic hypoxic-PH (12). In addition, DHEA treatment attenuates severe PAH in SuHx rats and protects against MCT-induced PAH in pneumonectomized rats (4, 59).

At the molecular level, DHEA inhibits PI3K/Akt, which phosphorylates and inactivates glycogen synthase kinase-3β. Glycogen synthase kinase-3β decreases the mitochondrial membrane potential, promotes apoptosis, and inhibits the activation of the transcription factor nuclear factor of the activated T cells, which downregulates the voltage-gated potassium (Kv) channels like Kv1.5, leading to cell depolarization, increased calcium levels, and cell proliferation. DHEA also inhibits the signal transducers and activators of transcription-3, one of the key mediators responsible for proliferative and antiapoptotic phenotypes in PAH, which also upregulates survivin proteins (102). DHEA has additionally been shown to attenuate PAH by inhibiting NADPH or glucose-6 phosphate dehydrogenase activity in pulmonary artery smooth muscle cells (PASMCs) (4, 25, 100). Alternatively, DHEA may inhibit RhoA/Rho-kinases (ROCK) signaling, which is known to contribute pathologically in numerous models of PH (59) (see below for more details).

Although data related to the use of DHEA in PAH are limited, DHEA treatment has been recently reported to improve 6-min walk test distance (6MWD), pulmonary hemodynamics, and the diffusing capacity of the lung for carbon oxide in patients with PH associated with chronic obstructive pulmonary disease (35).

Serotonin

Multiple studies have implicated serotonin (5-HT), a monoamine neurotransmitter found in the gastrointestinal tract, blood, and central nervous system, in the development of PAH (94, 140). Serotonin is produced in PAECs by tryptophan hydroxylase (TPH1) and acts at the 5-HT (1B and 2A) receptor and the serotonin receptor transporter (SERT or 5-HTT) to mediate constriction and proliferation of vascular smooth muscle cells (84, 94).

Treatment with the most potent 5-HT_1B antagonist LY393558, alone or in combination with fluoxetine and SB224289, has been shown to reduce 5-HT-induced pulmonary vasoconstriction in rats exposed to 2-wk hypoxia (94). C-122, a novel antagonist that blocks the 5-HT_2B receptor, has also been shown to lower pulmonary pressures, decrease RV hypertrophy, and reduce pulmonary vascular remodeling in MCT rat model of PAH (140). A recent study also demonstrated that the antagonist of 5-HT_2B receptor, SB204741, prevented heritable PAH (HPAH) (134). Additionally, RP5063, a multimodal dopamine (DA) and 5-HT modulator with high affinity for DA2/3/4 and 5-HT2A/2B/7 receptors and moderate affinity for SERT, has been recently reported to prevent MCT and SuHx models of PAH (10, 11). Moreover, supplementation with 5-HT_1B antagonists and 5-HTT antagonist, alone or in combination, increases apoptosis and reduces proliferation of PASMCs through downregulation of extracellular signal-regulated kinase-1/2 and pyruvate dehydrogenase kinase (PDK) signaling pathways (84). Although a recent study by De Raaf et al. (32) demonstrated that serotonin transporter is not required for the development of severe PH in SERT knockout (KO) rats exposed to SuHx, serotonin-targeting strategies remain a promising therapeutic option for the treatment of PAH.

RhoA/Rho-Kinase

The ROCK pathway was originally discovered in 1995 as an effector of the G protein RhoA. Increased RhoA/ROCK activity is implicated in a number of pathophysiological events ranging from abnormal vasoconstriction to promotion of vascular inflammation and remodeling, all of which are associated with numerous cardiovascular diseases, including PAH (25). ROCK inhibits calcium-independent myosin light chain phosphatase activity by phosphorylating myosin phosphatase-targeting subunit 1 and a smaller subunit M20, thus inducing vascular smooth muscle cell contraction (41). Additional vasoconstriction and remodeling are mediated by inhibition of eNOS, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 (98). Fasudil, the first generation RhoA/ROCK inhibitor, has been shown to suppress hypertension in both animals and humans (90, 116). Moreover, fasudil has been shown to lower pulmonary artery pressure, improve pulmonary vascular remodeling, and RV hypertrophy in rats with PAH induced by MCT and SuHx, as well as in mice with pulmonary fibrosis and PH induced by bleomycin (9, 41, 98). Most recently, the use of combination therapy with fasudil and SOD was reported to slow PAH progression in MCT and SuHx rats (51).

Clinical trials of fasudil on extensive background therapy have shown a significant improvement in pulmonary artery pressures and PVR in PAH patients (41). Two recent studies have also demonstrated that acute fasudil treatment reduces pulmonary pressures and PVR in 12 and 35 patients with congenital heart disease and severe PAH (81, 135). Lastly, the use of AT-877ER, an extended release formulation of fasudil, has also been recently reported to improve pulmonary hemodynamics in patients with PAH (42). However, these beneficial effects require further verification in future clinical trials.

Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a peptide hormone that is produced throughout the body and acts on type II G coupled-protein receptors (VPAC1 and VPAC2) to exert prominent vasodilation, antiproliferation, and anti-inflammatory properties via activation of cAMP and cGMP systems (137). Recent animal studies have shown that VIP KO mice developed moderate PAH, accompanied by RV hypertrophy, pulmonary vascular remodeling, and infiltration of perivascular inflammatory cells (112). Replenishment of VIP attenuated both vascular remodeling and RV hypertrophy in VIP KO mice (112).

Low serum concentrations of VIP have also been described in patients with PAH. These patients were reported as having received a significant improvement of pulmonary hemodynamics after chronic external VIP substitution via an aerosol (105). Other work by Leuchte et al. (77) also showed that inhalation of VIP (aviptadil) improved PVR and oxygenation in patients with PAH, patients with PH associated with lung disease, and patients with CTEPH. Because VIP is known to have a short half-life due to being rapidly inactivated by neuropeptidases (NEP) located on the lung surface, recent work from the same group evaluated the combined treatment with VIP and thiorphan, an NEP 24.11 inhibitor, in isolated rabbit lungs exposed to thromboxane A₂ mimetic U46619, which induces pulmonary vasoconstriction. Remarkably, thiorphan significantly augmented the hemodynamic effects of VIP on PH (78). Finally, inhalation of the cyclic VIP analog RO 25-1553 has also been shown to induce potent and sustained vasodilatory effects in ex vivo and in vivo models with hypoxia exposure, without detectable adverse effects (137). Still, the clinical effects of this type of treatment need to be further investigated.

Inhaled Nitrite

Nitrite ( $N O_{2}^{-}$ ) is reduced to form NO in blood and tissues by a variety of heme- and molybdopterrin-containing proteins (such as hemoglobin, myoglobin, neuroglobin, xanthine oxidase, sulfite oxidase, and mARC enzymes) (88). Inhaled and orally administered nitrite has been shown to reduce pulmonary pressures in sheep, mouse, and rat models of PH (20, 62, 75, 141) and has now advanced through phase 1 safety studies to phase 2A proof-of-concept studies in the catheterization laboratory (13, 14, 111). A recent study by Simon et al. (117) evaluated inhaled nitrite in 20 patients with PAH on extensive background therapy and in 10 and 6 patients with Groups 2 and 3 PH, respectively. While nitrite was safe, well tolerated, and reduced pulmonary pressures in all patients, the hemodynamic profile appeared most favorable in Groups 2 and 3 PH (117). This is based on a significant reduction in all pressures, including central venous, pulmonary artery, and pulmonary artery occlusion pressures (PAOPs). The significant drop in PAOP limited the decrease in PVR. Other investigators have recently reported that inhaled and intravenous nitrite also reduces PAOP during exercise in patients with Group 2 PH (particularly the subset of patients with heart failure with preserved ejection fraction), which is associated with improved exercise capacity (13, 14). This drug is now being evaluated by the National Heart, Lung, and Blood Institute Heart Failure Network and is under development by United Therapeutics (NCT02742129) (109).

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ANTIPROLIFERATIVE/ANTI-INFLAMMATORY

Bone Morphogenic Protein Receptor Type 2

Since the discovery of mutations in the gene encoding BMPR2 in families with PAH, BMPR2 has been studied extensively and has become a central player in PAH. BMPR2 is a member of the TGF-β signaling family. Mutations in BMPR2 have been found in 80% of patients with HPAH, as well as in 40% of patients with sporadic or idiopathic PAH (3). BMPR2 signaling regulates cell growth via stimulation of Smad1/5/8, which has downstream effects on Smad4. BMPR2 is involved in maintaining balance between the smooth muscle cells and the vascular endothelium. Loss of BMPR2 in PAECs has been shown to increase susceptibility of cells to apoptosis (126). Pulmonary endothelium-specific BMPR2 KO mice have also been shown to be predisposed to PAH development (60). Moreover, a recent study reported that mice bearing a heterozygous knockin allele of a human BMPR2 mutation, R899X, developed spontaneous PAH (87).

Therapeutic benefits targeting the BMPR2 pathway have been investigated greatly and have now progressed into clinical trials. High-throughput screening of 3,765 FDA-approved drugs has identified FK506 (tacrolimus), a calcineurin inhibitor often used in organ transplantation for immune suppression, as an activator of BMPR2. In addition to acting as a calcineurin inhibitor, FK506 also binds FK-binding protein-12, which is a repressor of BMP signaling, to activate BMPR2. FK506 has been shown to prevent the development of PAH in mice with endothelial deletion of BMPR2 and reverse established PAH in MCT and SuHx rat models (121). The use of low-dose FK506 has led to positive clinical results in patients with PAH in an ongoing phase 2A clinical trial, but these beneficial effects need to be further evaluated in the near future (120).

Enhancement of endothelial BMPR2 signaling with selective ligand BMP9 has also been recently reported to reverse established PAH in mice with heterozygous R899X mutation, as well as in MCT and SuHx rat models of PAH (87). In addition, ataluren, a drug that promotes ribosomal read-through of premature stop codons, was found to increase BMP-mediated miRNA processing in six out of eight patients with HPAH with nonsense mutations in BMPR2 and Smad9 (34). Other work has demonstrated that the immunoglobulin-Fc fusion protein of TGF-β (TGFBRII-Fc), which serves as a selective TGF-β 1/3 ligand trap, improves pulmonary hemodynamics, vascular remodeling, and survival in MCT rat, as well as in SuHx-exposed mice and rats (138). Restoration of BMPR2 signaling via activation of the transcription factor Forkhead box O1 with the chemotherapeutic agent paclitaxel has also been shown to reverse pulmonary vascular remodeling and RV hypertrophy in animal models of PAH (113). Furthermore, the elastase inhibitor elafin was recently reported to reverse severe PAH in SuHx rats via caveolin-1-dependent BMPR2 signaling (95). However, the clinical and hemodynamic effects of these BMPR2-targeting strategies are yet to be determined.

Bardoxolone Methyl

Triterpenoids are a family of electrophilic compounds found in nature (chrysanthemum flower) that covalently modify reactive thiols to signal anti-inflammatory and anticarcinogenic properties and have been used in Asian medicine for disease management (132). Bardoxolone methyl is a synthetic triterpenoid, and it has been shown to inhibit proliferation of PASMCs and exhibit anti-inflammatory effects via activation of Keap1/Nrf2 and downregulation of transcription factor NF-κB (132). While no published preclinical studies of bardoxolone methyl could be found at present, a 16-wk treatment with bardoxolone methyl on one or more background therapies was reported to improve 6MWD in an initial analysis of 24 PAH patients enrolled in an ongoing phase 2 LARIAT trial (NCT02036970) (99). Furthermore, a current phase 3 CATALYST trial (NCT02657356) is recruiting PAH patients associated with connective tissue disease to evaluate the effect of bardoxolone methyl. Other electrophilic compounds, such as nitro-fatty acids (NO₂-FAs), have also been shown to exert antiproliferative and anti-inflammatory effects via activation of Keap1/Nrf2 signaling pathway and inhibition of NF-κB (29, 131). NO₂-FAs also provide beneficial metabolic effects by serving as partial agonists of peroxisome proliferator-activated receptors (114). NO₂-FAs have additionally been shown to improve PH in mice exposed to hypoxia or high-fat diet (65, 71) and may now be tested in human PAH.

CCR5/CCL5

The G protein-coupled receptor CCR5 is a major coreceptor for HIV cell entry, and it has been recently linked to the progression of HIV-associated PH. Elevated CCR5 expression was found in lungs from patients with PAH, in mice with hypoxia-induced PH, and in SIV-infected macaques (6). CCR5 deficiency, as well as pharmacological inactivation of CCR5 by maraviroc, decreased the development of hypoxic PH in mice (6). CCR5 is activated by chemokines including CCL3, CCL4, and CCL5 (also known as regulation upon activation, normal T-cell expressed and secreted). Elevated CCL5 mRNA expression was found in PAECs from patients with PAH (33). However, no clinical trial targeting CCR5/CCL5 in PAH has been planned at present.

Dichloroacetate

It is becoming widely recognized that PASMCs in PAH are glycolytic and are subject to the Warburg effect, similar to transformed malignant cells. These cells become proliferative and resistant to apoptosis. A number of new drugs are designed to target metabolic pathways to reverse this process. One proposed check point controlling the entry of pyruvate into Krebs cycle is pyruvate dehydrogenase, which is necessary for efficient glucose oxidative metabolism. This enzyme is inhibited by PDK, which appears to be upregulated in glycolytic smooth muscle cells from patients and pre-clinical models of PAH. Inhibition of PDK with dichloroacetate (DCA) has been shown to prevent and reverse pulmonary vascular remodeling in rats with PH induced by chronic hypoxia and MCT (91, 93). DCA was shown to increase apoptosis and suppress proliferation by depolarizing mitochondria, which causes the release of H₂O₂ and cytochrome c, leading to the subsequent restoration of expression and function of Kv channels (91, 93). DCA has also been shown to attenuate PAH through inhibition of nuclear factor of the activated T cells, inactivation of hypoxia-inducible factor-1α, as well as upregulation of Cu/Zn SOD activity and mitochondria-dependent apoptosis in experimental PH models (50, 80, 123). A recently completed phase 1 clinical trial by Michelakis et al. (92) evaluated chronic oral DCA administration on background therapy in 20 patients with PAH. While DCA administration led to an improvement in pulmonary artery pressure, PVR, and functional capacity, DCA resistance has been found in patients with sirtuin-3 (SIRT3) and uncoupling protein 2 variants, both of which predict decreased protein activity and have been linked to the development of PAH (92, 101).

Leukotriene B4

Leukotriene B4 (LTB4) is a leukotriene produced from arachidonic acid metabolism via the 5-lipoxygenase pathway. It has been implicated in several inflammatory diseases, including asthma, atherosclerosis, stroke, and, myocardial infarction (55, 56, 63, 119). A recent study by Tian et al. found high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for LTB4, in Sugen/athymic rat model of severe PH and in patients with PAH (127). In this study, LTB4 was found to induce apoptosis in PAECs through inhibition of the endothelial sphingosine kinase-1 (Sphk1)/eNOS pathway, as well as to stimulate proliferation and hypertrophy of PASMCs. Blocking LTB4, either through bestatin-mediated inhibition of LTB4 biosynthesis or through blocking BLT1, a high-affinity receptor for LTB4, reversed established PH in Sugen/athymic and MCT rats (127). LTB4 has been additionally shown to promote PH pathogenesis through promoting proliferation, migration, and differentiation of adventitial fibroblast via upregulation of p38 MAPK and NADPH oxidase 4 (Nox4) signaling pathways (107). Blocking LTB4 synthesis and inhibition of p38 MAPK by bestatin and SB203580, respectively, reduced fibroblast expansion and Nox4 expression in experimental PH (107). Moreover, it was shown that bleomycin treatment leads to LTB4-meidated macrophage influx and PH. Inhibition of LTB4 formation with zileuton (5-lipoxygenase inhibitor) and SC57461A (LTA4H inhibitor) prevented the development of PH in rat pups exposed to bleomycin (36). Currently, the effect of bestatin (ubenimex) is being examined in a phase 2 clinical trial (LIBERTY Study) in patients with PAH (NCT02664558). Furthermore, Bhat et al. (11) demonstrated that administration of the serotonin receptor antagonist RP5063 reduced LTB4 in SuHx rat model of PAH, suggesting a cross talk between the leukotriene and serotonin pathway in the regulation of PH. Preparations for a phase 2 clinical trial of RP5063 by Reviva Pharmaceuticals for patients with PAH are currently underway.

Mammalian Target of Rapamycin

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is involved in the regulation of cell growth, proliferation, and survival. Krymskaya et al. (72) have recently demonstrated that upregulation of mTOR activity and activation of both complexes, the rapamycin-sensitive mTOR complex 1 (mTORC1; mTOR-raptor), which supports cell growth, and the rapamycin-insensitive mTORC2 (mTOR-rictor), which promotes cell survival, are required for the proliferation of PASMCs under chronic hypoxia. Additional studies from the same group further demonstrated that hypoxia-induced activation of NADPH oxidase (Nox4) upregulates mTORC2, which facilitates mTORC1 activation and PASMC proliferation via downregulation of the energy sensor AMPK (47). Treatment with the mTOR kinase inhibitor PP242 reversed pulmonary vascular remodeling in hypoxia-exposed rats and improved RV structure and function in SuHx rats (47, 104). Additionally, attenuation of hypoxia-induced PH has been reported in Akt1-deficient mice, in smooth muscle-specific mTOR conditional and inducible KO mice, and in transgenic mice of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which is a repressor of Akt activity, underlining the importance of PTEN/Akt1/mTOR signaling pathway in PH (125). Furthermore, molecular and pharmacology-based analyses have uncovered a HIPPO/mTOR pathway in PH as inactivation of HIPPO central component large tumor suppressor 1 (LATS1) and consequent upregulation of its reciprocal effector Yes-associated protein (Yap) are required for AKT/mTOR-mediated proliferation and survival of PASMCs (73). Other work has shown that elevated circulating levels of aldosterone observed in patients of PAH are associated with mTORC1 activation and the subsequent survival and proliferation of PASMCs (1, 89). Combination treatment with Raptor-small interfering RNA and the pharmacological inhibitor spironolactone prevented and reversed MCT and SuHx models of PAH (1). A recent pilot study reported that the mTOR inhibitor, everolimus, improved PVR and 6MWD in 8 out of 10 patients with PAH or CTEPH (115). ABI-009, an albumin-bound mTOR inhibitor, is now being evaluated in patients with severe PAH (NCT02587325).

Peroxisome Proliferator-Activated Receptor-γ

Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of nuclear hormone receptor superfamily and a transcription factor that plays a major beneficial role in cardiovascular homeostasis and glucose metabolism (8, 103). It is highly expressed in endothelial and smooth muscle cells in the lung. Decreased expression levels of PPARγ have been shown in lungs from SuHx- and hypoxia-exposed rats, as well as in lungs from patients with severe PAH and patients with chronic obstructive pulmonary disease (5, 66). Loss of PPARγ in PAECs was reported to reduce PAEC function and survival via decreased apelin expression (2). Mice with targeted deletion of PPARγ in endothelial cells were also found to suffer persisted PH compared with wild-type mice exposed to hypoxia (49). Additionally, Hansmann et al. (52) have shown that vasoprotective PPARγ acts downstream of BMPR2 and that mice with targeted deletion of PPARγ in arterial smooth muscle cells spontaneously developed PAH.

PPARγ agonist rosiglitazone has recently been shown to attenuate hypoxia-induced PH in mice and rats (66, 85, 96). Rosiglitazone was found to decrease ET-1-induced pulmonary vasoconstriction in hypoxic rats (85). Most recently, treatment with rosiglitazone was also reported to reversed PAH through inhibition of TGFβ1-Stat3-FoxO1 pathways in TGFβ1-overexpreesing mice (19). Furthermore, PPARγ activation by rosiglitazone was reported to reverse insulin resistance-associated PH in apolipoprotein E KO mice on a high-fat diet (52). No plans for clinical trials of rosiglitazone for PAH have been reported to date.

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FUTURE PERSPECTIVES

In addition to emerging opportunities discussed above, epigenetics is a rapidly expanding filed in PAH. Recently, hypermethylation of BMPR2 promoter in patients with HPAH was discovered, and it was found to inhibit BMPR2 expression (83). Histone deacetylation is linked to downregulation of SOD in PH (67, 97). Several studies have demonstrated that the use of histone deacetylase (HDAC) inhibitors improves established PAH in experimental models (15, 21, 23, 26, 76, 139); however, controversial results were reported as trichostatin A, a pan-HDAC inhibitor, was found ineffective in rats with MCT-, SuHx-, and pulmonary artery banding-induced PAH (31). Moreover, therapies targeting vascular proliferation with the antineoplastic receptor tyrosine kinase inhibitors have been explored. While a multicenter phase 3 trial of the tyrosine kinase inhibitor imatinib demonstrated improvement in 6MWD and PVR, several side effects were observed and the treatment was discontinued in one out of three of the patients. This led the authors to conclude that the use of this therapy should be discouraged, as the side effects outweigh the benefit (39, 57). Lastly, Sphk1 (24), angiotensin-converting enzyme 2 (30, 38, 70, 82), SIRT3 (75, 101), gremlin 1 (Grem1) (18, 28, 40, 46, 133), as well as miRNAs [reviewed in depth by Chun et al. (27)] may present as potential therapeutic targets for PH management in the future.

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SUMMARY

Apart from the current FDA-approved therapies, recent studies have advanced our knowledge and understanding of how inflammation, mitochondrial dysfunction, proliferation, and vasodilation are integrated into the modulation of PAH (Fig. 3). It is noteworthy that some of the new approaches/targets of PAH, such as the use of DHEA, inhaled nitrite, inhalation of VIP, and PPARγ agonists, may provide new insights in the treatment of other forms of PH. Substantial progresses in the understanding of roles of epigenetic modifications and miRNAs in PH also provide potential translational options for the treatment of PH in the future. Finally, as genders and individuals with phenotypic variations are likely to have different response to drug treatments, it is proposed that genotyping with precision medicine may be considered in future studies to maximize beneficial response to specific treatments and to provide significant positive impact on improving outcomes in patients with PH.

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Fig. 3.

Emerging targets and therapies for PAH. TGF-β, transforming growth factor-β; SMC, smooth muscle cells; LTB4, leukotriene B4; mTOR, mammalian target of rapamycin.

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GRANTS

M. T. Gladwin receives research support from National Heart, Lung, and Blood Institute Grants 2R01-HL-098032, 1R01-HL-125886-01, P01-HL103455, T32-HL-110849, and T32-HL-007563 and Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania. Y. C. Lai receives support from American Heart Association Grant 17SDG33400233.

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DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

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AUTHOR CONTRIBUTIONS

M.K.H., M.T.G., and Y.-C.L. drafted manuscript; M.K.H., A.L., M.T.G., and Y.-C.L. edited and revised manuscript; M.K.H., M.T.G., and Y.-C.L. approved final version of manuscript; Y.-C.L. prepared figures.

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ACKNOWLEDGMENTS

We thank Dr. Sergei Snovida for helpful comments on the manuscript and Elfy Chiang for assistance and production of the figures.

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(1 citation) ClinicalTrials.gov - NCT02664558
(1 citation) ClinicalTrials.gov - NCT02657356
(1 citation) ClinicalTrials.gov - NCT02036970

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Grant ID: T32 HL007563
186 publications
Grant ID: P01 HL103455
260 publications

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Emerging therapeutics in pulmonary hypertension.

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Emerging therapeutics in pulmonary hypertension

Matthew K. Hensley

Andrea Levine

Mark T. Gladwin

Yen-Chun Lai

Abstract

INTRODUCTION

DEFINITION OF PH

CURRENT THERAPIES FOR PH

EMERGING TARGETS AND THERAPIES FOR PAH

VASODILATORS

Apelin

Dehydroepiandrosterone

Serotonin

RhoA/Rho-Kinase

Vasoactive Intestinal Peptide

Inhaled Nitrite

ANTIPROLIFERATIVE/ANTI-INFLAMMATORY

Bone Morphogenic Protein Receptor Type 2

Bardoxolone Methyl

CCR5/CCL5

Dichloroacetate

Leukotriene B4

Mammalian Target of Rapamycin

Peroxisome Proliferator-Activated Receptor-γ

FUTURE PERSPECTIVES

SUMMARY

GRANTS

DISCLOSURES

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

REFERENCES

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Funding

NHLBI NIH HHS (2)﻿

NHLBI NIH HHS (2)