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• W2887947601 abstract "HomeCirculationVol. 137, No. 22New Therapeutic Approaches in Pulmonary Arterial Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNew Therapeutic Approaches in Pulmonary Arterial HypertensionThe Pantheon Is Getting Crowded R. James White, MD, PhD and Martin R. Wilkins, MD R. James WhiteR. James White Aab Cardiovascular Research Institute and Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, NY (R.J.W.). Search for more papers by this author and Martin R. WilkinsMartin R. Wilkins Department of Medicine, Imperial College London, UK (M.R.W.). Search for more papers by this author Originally published29 May 2018https://doi.org/10.1161/CIRCULATIONAHA.118.032700Circulation. 2018;137:2390–2392Article, see p 2371Pulmonary arterial hypertension (PAH) is a rare disease that nonetheless casts a large shadow because it most commonly afflicts young women in its idiopathic form and remains a disabling complication of scleroderma and congenital heart disease.1 Treatment advances in the last 20 years have been striking, but high-risk patients still succumb at a rate of 15% annually.2 Moreover, our most effective therapy, the continuous infusion of parenteral prostacyclin, is cumbersome and expensive. Although oral treatments are available, a desperate need remains for convenient therapies that further improve survival and quality of life.3Observations in the last decade have linked the unbridled vascular cell proliferation evident on lung histology with a shift in cell metabolism from mitochondrial oxidative phosphorylation to anaerobic glycolysis reminiscent of cancer (the Warburg effect).4 Moreover, as with cancer, this glycolytic switch accompanies broader changes in cell metabolism that provide the building blocks for rapid cellular proliferation, including glutamine.5 In this issue of Circulation, Dumas et al6 propose that the accumulation of glutamine ultimately stimulates N-methyl-d-aspartate (NMDA) receptors on pulmonary vascular endothelial and smooth muscle cells and so contributes to PAH pathogenesis.NMDA receptor activation is a key mediator of a host of central nervous system processes, from long-term potentiation to traumatic brain injury, and NMDA receptor blockers have been studied as a strategy to limit the magnitude of ischemic stroke. The authors note that NMDA receptor activation has previously been reported to facilitate cancer cell proliferation, but their compelling observations in the diseased pulmonary circulation are highly novel. Using mass spectroscopy, they demonstrate that the vascular PAH lesions identified within end-stage human lung tissue accumulate glutamine and cleave this to the neurotransmitter glutamate. This accumulation of glutamate occurs most clearly in the smaller pulmonary arterioles, a principal target for current disease therapies. They show that glutamate acts at NMDA receptors on human pulmonary endothelial and smooth muscle cells (SMCs). They found that the key regulatory subunit for NMDA receptor signaling, the short GluN1 protein, was upregulated in the PAH pulmonary arteries. GluN1 receptor phosphorylation was particularly prominent in SMC lesions classically referred to as medial hypertrophy. In vitro experiments using human cells (both endothelial and SMC) demonstrated the specialized machinery for uptake and release of glutamate. Although not a focus of this article, the authors discuss the intriguing possibility that this is synaptic-like communication outside the central nervous system.In vitro, the classic PAH signaling molecule, endothelin, independently increased both glutamate release and GluN1 phosphorylation in human pulmonary artery SMCs, suggesting that SMCs utilize this glutamate pathway to mediate signaling that is clearly associated with disease. Similarly, platelet-derived growth factor, a growth factor implicated in PAH pathogenesis, stimulated GluN1 phosphorylation. NMDA receptor blockers reduced the platelet-derived growth factor–mediated proliferation of human pulmonary SMCs.Dumas et al6 complement their work in human tissue and cells by conducting studies in animal models. They describe the rationale for each experiment and in so doing underscore the advantages and limitations of their chosen approaches. Although murine hypoxia produces only modest and readily reversible vascular changes, they use this model system to demonstrate that vascular smooth muscle GluN1 knockout mice are resistant to the development of hypoxic pulmonary vascular remodeling and hypoxic pulmonary hypertension (PH). They then used a well-characterized, centrally acting NMDA receptor blocker, MK-801, in a therapeutic trial for rats with monocrotaline-induced PH. It is important to note that male rats were allowed to develop PH until day 14 before the authors started treatment with MK-801. After 7 days of treatment, remodeling of pulmonary arteries was reduced, and there were corresponding improvements in right ventricular function and myocardial histology. Their findings support the hypothesis that NMDA receptor blockade can reduce SMC proliferation and the muscularization of small pulmonary arterioles observed in this experimental model.The authors have clearly identified glutamate-dependent NMDA-receptor GluN1 phosphorylation as yet another potential target in PAH. We presently find ourselves at an interesting place in the development of new treatments for PAH: The challenge is not a shortage of drug targets but rather how to prioritize and test those identified. Indeed, the current list of drug targets in PAH seems as daunting as the list of Roman gods: Who is really worthy of worship (and when)? Funding bodies and pharmaceutical sponsors are struggling with this. Repurposing an already licensed drug can help the argument for pursuing a target, but the current clinically available NMDA receptor antagonists are not suitable for a chronic condition such as PAH because they have unacceptable central effects. New drug development will be required for PAH, and a key property will be that the molecule does not cross the blood–brain barrier. As the authors acknowledge, a better understanding of the NMDA subtypes mediating the vascular effects of NMDA blockade would also be helpful with respect to limiting possible peripheral side effects of NMDA blockade, such as bleeding or hypoglycemia.Beyond the specifics of medicinal chemistry for NMDA antagonists, new drug development in PAH, as in every disease, is an expensive and perilous process. Further studies are needed to inspire confidence before determining the worth of NMDA receptors as a target. The limitations of animal models of PH in selecting suitable drug targets have been well rehearsed.7 The monocrotaline (MCT) model has received particular criticism of late.8 Often a single drug is sufficient to almost completely reverse experimental PH and, in some cases, the accompanying vascular pathology. With the exception of a few patients, this is not the case for the human condition. Indeed, the current approach to treating patients with PAH relies on (initial) combination therapy, and new treatments are investigated as add-on therapies.9 Thus, the overestimation of therapeutic benefit in the MCT model limits its utility as a translational platform for drug development in the contemporary era. MCT together with pneumonectomy10 and Sugen with hypoxia11 create more severe PH and right ventricular failure; therefore, they offer the potential to estimate the size of a signal for efficacy on a background of approved therapy. We (R.J.W.) have demonstrated the ability to observe combination benefits from 2 approved therapies in female rats with PH in the pneumonectomy and MCT model,12 and others have demonstrated similar findings in male rats exposed to Sugen-hypoxia.13 Both models also cause disease in females14 (which MCT alone does not), and this seems particularly relevant in a disease that afflicts far more females than males.That said, the best model of the human condition is the patient with PAH. Expression of the drug target in diseased tissue is just the first step. Looking forward, it would be helpful to know at what stage of disease the expression of glutaminase, glutamate transporters, or GluN1 is upregulated and whether there is variation among patients. Lung tissue is only available at the end stage of the disease, but we are just scratching the surface of what can be learned from peripheral blood samples, especially when such samples are coupled to advanced methods for cell isolation, preservation, and culture. For example, useful information may be gathered from isolating circulating blood-outgrowth endothelial cells or skin fibroblasts from patients with PAH.15,16 Alternatively, experiments to induce pluripotent stem cells from patients with PAH toward an SMC phenotype would allow for more specific interrogation about the relevance of the present finding to patients with (presumably) earlier manifestations of the vascular pathology.17With increasing interest in personalized medicine, information from human samples could assist the selection of patients for a small, early-phase, therapeutic clinical trial of NMDA receptor blockade. Selection criteria might include evidence for increased glutamate synthesis or GluN1 receptor phosphorylation in peripheral blood mononuclear cells, and then early stage studies might adjust the dose of investigational drug to achieve a predefined pharmacodynamic effect (eg, inhibition of GluN1 phosphorylation in those cells). This strategy would serve to enrich the clinical research study with participants who have evidence for target expression and increase confidence in the chosen dose for a long-term, functional assessment of an NMDA receptor blocker in PAH. Especially in a rare disease with a limited number of patients to participate, it is time for more efficient clinical research designs that will then set the stage for personalized (and likely more cost-effective) approaches to a new drug’s utilization.Drug development is always risky, but the challenges in PAH are especially daunting. Aside from finding eligible patients, current surrogate end points have a substantial signal/noise ratio, and even early functional trials will likely require 6 to 9 months to demonstrate meaningful effects. In the midst of these Herculean design challenges, there is an impressive list of drugable targets. There are enormous real and opportunity costs in deciding which of these promising targets might merit progression to early phase human clinical trials. The novel observations of Dumas et al6 suggest that NMDA receptor activation integrates many pathological facets of PAH, including excess endothelin and platelet-derived growth factor signaling, perturbed cell metabolism, and SMC proliferation. Their data have nominated NMDA receptor antagonism for entry to the pantheon of novel strategies for treating PAH. In the absence of genetic clues, we would suggest that full admittance requires further work in cells from living patients with PAH and relevant, more demanding animal models.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.http://circ.ahajournals.orgR. James White, MD, PhD, Aab Cardiovascular Research Institute and Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, 400 Red Creek Dr, Rochester, NY 14623. E-mail [email protected]References1. Humbert M, Lau EM, Montani D, Jaïs X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension.Circulation. 2014; 130:2189–2208. doi: 10.1161/CIRCULATIONAHA.114.006974.LinkGoogle Scholar2. Boucly A, Weatherald J, Savale L, Jais X, Cottin V, Prevot G, Picard F, de Groote P, Jevnikar M, Bergot E, Chaouat A, Chabanne C, Bourdin A, Parent F, Montani D, Simonneau G, Humbert M, Sitbon O. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension.Eur Respir J. 2017; 50:1700889. doi: 10.1183/13993003.00889-2017.CrossrefMedlineGoogle Scholar3. James White R, Lannan KL, Phipps RP. Drug discovery in pulmonary arterial hypertension: attacking the enigmatic root of a deadly weed.Drug Discov Today. 2014; 19:1226–1229. doi: 10.1016/j.drudis.2014.04.008.CrossrefMedlineGoogle Scholar4. Archer SL, Fang YH, Ryan JJ, Piao L. Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension.Pulm Circ. 2013; 3:144–152. doi: 10.4103/2045-8932.109960.CrossrefMedlineGoogle Scholar5. Piao L, Fang YH, Parikh K, Ryan JJ, Toth PT, Archer SL. Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.J Mol Med (Berl). 2013; 91:1185–1197. doi: 10.1007/s00109-013-1064-7.CrossrefMedlineGoogle Scholar6. Dumas SJ, Bru-Mercier G, Courboulin A, Quatredeniers M, Rucker-Martin C, Antigny F, Nakhleh MK, Ranchoux B, Gouadon E, Vinhas M-C, Vocelle M, Raymond N, Dorfmüller P, Fadel E, Perros F, Humbert M, Cohen-Kaminsky S. NMDA-type glutamate receptor activation promotes vascular remodeling and pulmonary arterial hypertension.Circulation. 2018; 137:2371–2389. doi: 10.1161/CIRCULATIONAHA.117.029930.LinkGoogle Scholar7. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure.Am J Physiol Lung Cell Mol Physiol. 2009; 297:L1013–L1032. doi: 10.1152/ajplung.00217.2009.CrossrefMedlineGoogle Scholar8. Bauer NR, Moore TM, McMurtry IF. 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White RJ, Meoli DF, Swarthout RF, Kallop DY, Galaria II, Harvey JL, Miller CM, Blaxall BC, Hall CM, Pierce RA, Cool CD, Taubman MB. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension.Am J Physiol Lung Cell Mol Physiol. 2007; 293:L583–L590. doi: 10.1152/ajplung.00321.2006.CrossrefMedlineGoogle Scholar11. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension.Circulation. 2010; 121:2747–2754. doi: 10.1161/CIRCULATIONAHA.109.927681.LinkGoogle Scholar12. Lachant D, Haight D, Glickman S, Akers S, Ambrosini R, Staicu S, White R. Combination ambrisentan and tadalafil preserve vascular volume quantified by micro CT better than either monotherapy.Am J Respir Crit Care Med. 2016; 193:A3892.Google Scholar13. Cavasin MA, Demos-Davies KM, Schuetze KB, Blakeslee WW, Stratton MS, Tuder RM, McKinsey TA. 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Patient-specific iPSC-derived endothelial cells uncover pathways that protect against pulmonary hypertension in BMPR2 mutation carriers.Cell Stem Cell. 2017; 20:490e5–504e5.CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Rosenkranz S, Feldman J, McLaughlin V, Rischard F, Lange T, White R, Peacock A, Gerhardt F, Ebrahimi R, Brooks G, Satler C and Frantz R (2022) Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial, The Lancet Respiratory Medicine, 10.1016/S2213-2600(21)00032-1, 10:1, (35-46), Online publication date: 1-Jan-2022. Zhou X, Huang F, Li Y, Huang H and Wu Q (2021) SEDT2/METTL14-mediated m6A methylation awakening contributes to hypoxia-induced pulmonary arterial hypertension in mice, Aging, 10.18632/aging.202616, 13:5, (7538-7548), Online publication date: 15-Mar-2021. Lachant D, Meoli D, Haight D, Staicu S, Akers S, Glickman S, Ambrosini R, Champion H and White R (2019) Combination therapy improves vascular volume in female rats with pulmonary hypertension, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.00450.2018, 317:4, (L445-L455), Online publication date: 1-Oct-2019. May 29, 2018Vol 137, Issue 22 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.032700PMID: 29844072 Originally publishedMay 29, 2018 Keywordstranslational medical researchpulmonary hypertensionEditorialsNMDA receptorsPDF download Advertisement SubjectsAnimal Models of Human DiseaseCell Signaling/Signal TransductionPulmonary BiologyVascular Biology" @default.
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