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Aging and disease
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Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review
Ying Xiao1, Pei-Pei Chen1, Rui-Lin Zhou2, Yang Zhang1, Zhuang Tian1,*, Shu-Yang Zhang1,*
1Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2School of Medicine, Tsinghua University, Beijing 100084, China
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Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Management for PAH treatment includes improving symptoms, enhancing quality of life, and extending survival rate. Existing drugs developed to treat the disease have resulted in enormous economic and healthcare liabilities. The estimated cost for advanced PAH has exceeded $200,000 per year. The pathogenesis of PAH is associated with numerous molecular processes. It mainly includes germline mutation, inflammation, dysfunction of pulmonary arterial endothelial cells, epigenetic modifications, DNA damage, metabolic dysfunction, sex hormone imbalance, and oxidative stress, among others. Findings based on the pathobiology of PAH may have promising therapeutic outcomes. Hence, faced with the challenges of increasing healthcare demands, in this review, we attempted to explore the pathological mechanisms and alternative therapeutic targets, including other auxiliary devices or interventional therapies, in PAH. The article will discuss the potential therapies of PAH in detail, which may require further investigation before implementation.

Keywords pulmonary arterial hypertension      right ventricular dysfunction      hemodynamics      therapy advances     
Corresponding Authors: Zhuang Tian,Shu-Yang Zhang   
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These authors contributed equally to this work.

Just Accepted Date: 16 January 2020  
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Ying Xiao
Pei-Pei Chen
Rui-Lin Zhou
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Zhuang Tian
Shu-Yang Zhang
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Ying Xiao,Pei-Pei Chen,Rui-Lin Zhou, et al. Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review[J]. Aging and disease, 10.14336/AD.2020.0111
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GeneGene IDChromosomeDiseaseFunctionNameRefs
Member of the TGF-β receptor familyBone morphogenetic protein receptor type 2[29]
Receptor for the TGF-β superfamilyActivin A receptor-like type 1 (ALK1)[116]
ENG20229q34.11HHT/PAHCoreceptor of the TGF-β familyEndoglin[118]
SMAD9409313q13.3HPAHTransduces signals from the TGF-β familySMAD family member 9[119]
Encodes the TASK-1 channel, contributes to the membrane potentialPotassium two-pore domain channel subfamily K member 3[120]
EIF2AK444027515q15.1PVOD/PCHPhosphorylates eukaryotic translation initiation factor-2 (EIF2)Eukaryotic translation initiation factor 2 alpha kinase 4[121]
TBX4949617q23.2Small patella syndrome,
PAH in children
Involved in the development of lung diseaseT-box 4[14]
Binds the TGF-β receptorBone morphogenetic protein 9 or growth differentiation factor 2
Table 1  Gene variants associated with pulmonary arterial hypertension.
Figure 1.  Activation of BMP signaling with or without mutated BMPR2 and the pharmacological mechanism of FK506. BMP signaling in the presence of normal or mutated dysfunctional BMPR2. Mutated BMPR2 protein disturbs the dissociation of FKBP12-calcineurin from BMPR1 when stimulated by activating doses of BMPs. FK506 binds to FKBP12 and promotes the dissociation of FKBP12-calcineurin from BMPR type 1 receptors and then activates the downstream signaling pathway. BMP: bone morphogenetic protein; FKBP12: FK506-binding protein 12.
ParticipantsStudy designStudy durationPrimary outcome measureOutcome
Tacrolimus (FK506)Activator of BMP signalingNCT0164794523 patients with PAHSingle center, phase Ⅱ randomized, placebo-controlled study16 weeksSafety of low-dose FK-506 in PAHCompleted
TocilizumabHumanized anti-IL6R antibodyNCT0267694729 patients with group 1 PAHOpen-label phase II trial6 monthsSafety in terms of the incidence and severity of adverse eventsCompleted
AnakinraRecombinant IL-1 receptor antagonistNCT030570286 patients with stable PAH and RV failureSingle-arm, open-label, phase IB/II pilot study14 daysChange in exercise capacity as determined by peak oxygen consumption and ventilatory efficiencyCompleted
RituximabAnti-CD20 antibodyNCT01086540SSc-PAHDouble-blind, placebo-controlled, phase Ⅱ, multicenter, randomized trial48 weeksChange from baseline in 6MWDActive, not recruiting
Dichloroacetic acid
Inhibition of pyruvate dehydrogenase kinaseNCT0108352420 adult patients with IPAHPhase I, open-label, two-center study28 weeksSafety and tolerability of DCACompleted
Apabetalone (RVX-208)BET inhibitorNCT03655704Estimated 10 participantsEarly phase Ⅰ, two-center, open-label trial16 weeksChange in PVRRecruiting
OlaparibPARP1 inhibitorNCT03251872Estimated 6 participantsOpen-label, early phase I trial16 weeksChange in PVRRecruiting
AnastrozoleEstrogen inhibitorNCT0154533618 participantsDouble-blind, placebo-controlled, phase II study3 monthsPlasma estradiol (E2) level, tricuspid annular plane systolic excursion (TAPSE)Completed
MetforminMultifunctional aromatase inhibitor and AMPK activatorNCT03617458160 participantsPhase II, 2x2 factorial, randomized, blinded trial12 weeksChange from baseline in 6MWDRecruiting
ImatinibSelective tyrosine kinase inhibitorNCT0139249517 participantsOpen-label, phase III, nonrandomized trial144 weeksNumber of patients with adverse event and deathsTerminated for severe adverse effects
Dimethyl fumarateNuclear factor erythroid 2-related factor 2 (Nrf2) activatorNCT0298108234 participants with SSc-PAHDouble-blinded, phase I, placebo-controlled pilot study24 weeksImprovement in 6MWDRecruiting
Bardoxolone methylNrf2 pathway-activating agentNCT02657356202 participants with CTD-PAHPhase III, double-blind, randomized, placebo-controlled trial24 weeksChange from baseline in 6MWDNot recruiting
Gene-enhanced EPCs (PHACeT trial)Cell therapyNCT004690277 participants with PAHPhase I, open-label, dose-escalation study5 yearsTolerability and safety of the injection of genetically engineered progenitor cellsCompleted
Pulmonary artery denervation (PADN)Inhibitor of sympathetic stimulationNCT02284737Estimated 270 participantsPhase IV, prospective, multicenter, randomized control trial6 monthsPAH-related events, death including lung transplantation, atrial septostomy, worsening of PAHRecruiting
Table 2  Clinical trials and potential therapeutic targets in pulmonary arterial hypertension.
Figure 2.  Pathobiology of PAH and potential therapeutic targets. Pathological mechanisms and potential therapeutic targets of PAH. The pulmonary artery wall consists of three structural layers, including the adventitia, media, and intima. Various pathogenic factors, such as gene mutations, drugs/poisons, and hypoxia, can induce pulmonary arteriole vascular vasoconstriction, characterized by luminal stenosis, endothelial dysfunction, inflammation, infiltration, etc., ultimately causing RHF. The endothelin-1, prostacyclin, and nitric oxide pathways have been targeted in clinical practice and are three pivotal pathways approved in PAH management. Potential therapeutic targets are emerging as the pathobiology of PAH is revealed. AS: atrial septostomy; BAS: balloon atrial septostomy; PADN: pulmonary artery denervation; ECMO: extracorporeal membrane oxygenation.
[1] Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F (2011). Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol, 8:443-455.
[2] Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. (2015). 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J, 46:903-975.
[3] Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. (2013). Updated Clinical Classification of Pulmonary Hypertension. Journal of the American College of Cardiology, 62:D34-D41.
[4] Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JS, Vrapi F, et al. (2009). Connective tissue disease-associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med, 179:151-157.
[5] Peacock AJ, Murphy NF, McMurray JJ, Caballero L, Stewart S (2007). An epidemiological study of pulmonary arterial hypertension. Eur Respir J, 30:104-109.
[6] Ghofrani HA, Grimminger F, Grunig E, Huang Y, Jansa P, Jing ZC, et al. (2016). Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med, 4:361-371.
[7] Hachulla E, Jais X, Cinquetti G, Clerson P, Rottat L, Launay D, et al. (2018). Pulmonary Arterial Hypertension Associated With Systemic Lupus Erythematosus: Results From the French Pulmonary Hypertension Registry. Chest, 153:143-151.
[8] D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. (1991). Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med, 115:343-349.
[9] Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. (2006). Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med, 173:1023-1030.
[10] Klinger JR, Elliott CG, Levine DJ, Bossone E, Duvall L, Fagan K, et al. (2019). Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. Chest, 155:565-586.
[11] Frost A, Badesch D, Gibbs JSR, Gopalan D, Khanna D, Manes A, et al. (2019). Diagnosis of pulmonary hypertension. Eur Respir J, 53.
[12] Hoeper M, McLaughlin V, Barberá J, Frost A, Ghofrani H, Peacock A, et al. (2016). Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med, 4:894-901.
[13] Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. (2019). Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J, 53.
[14] Galambos C, Mullen MP, Shieh JT, Schwerk N, Kielt MJ, Ullmann N, et al. (2019). Phenotype characterisation of mutation and deletion carriers with neonatal and paediatric pulmonary hypertension. The European respiratory journal, 54:undefined.
[15] Wang X, Lian T, Jiang X, Liu S, Li S, Jiang R, et al. (2019). Germline mutation causes idiopathic pulmonary arterial hypertension. The European respiratory journal, 53.
[16] Long L, Ormiston ML, Yang X, Southwood M, Graf S, Machado RD, et al. (2015). Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med, 21:777-785.
[17] Morine KJ, Qiao X, York S, Natov PS, Paruchuri V, Zhang Y, et al. (2018). Bone Morphogenetic Protein 9 Reduces Cardiac Fibrosis and Improves Cardiac Function in Heart Failure. Circulation, 138:513-526.
[18] Tu L, Desroches-Castan A, Mallet C, Guyon L, Cumont A, Phan C, et al. (2019). Selective BMP-9 Inhibition Partially Protects Against Experimental Pulmonary Hypertension. Circ Res, 124:846-855.
[19] Evans JD, Girerd B, Montani D, Wang XJ, Galie N, Austin ED, et al. (2016). BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Lancet Respir Med, 4:129-137.
[20] Hong JH, Lee GT, Lee JH, Kwon SJ, Park SH, Kim SJ, et al. (2009). Effect of bone morphogenetic protein-6 on macrophages. Immunology, 128:e442-450.
[21] Sawada H, Saito T, Nickel NP, Alastalo TP, Glotzbach JP, Chan R, et al. (2014). Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J Exp Med, 211:263-280.
[22] Pickup MW, Hover LD, Polikowsky ER, Chytil A, Gorska AE, Novitskiy SV, et al. (2015). BMPR2 loss in fibroblasts promotes mammary carcinoma metastasis via increased inflammation. Mol Oncol, 9:179-191.
[23] van der Bruggen CE, Happe CM, Dorfmuller P, Trip P, Spruijt OA, Rol N, et al. (2016). Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle. Circulation, 133:1747-1760.
[24] Hemnes AR, Brittain EL, Trammell AW, Fessel JP, Austin ED, Penner N, et al. (2014). Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med, 189:325-334.
[25] Cogan JD, Pauciulo MW, Batchman AP, Prince MA, Robbins IM, Hedges LK, et al. (2006). High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med, 174:590-598.
[26] Morrell NW, Aldred MA, Chung WK, Elliott CG, Nichols WC, Soubrier F, et al. (2018). Genetics and genomics of pulmonary arterial hypertension. Eur Respir J.
[27] Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA, 3rd, et al. (2001). Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med, 345:319-324.
[28] Liu D, Wu WH, Mao YM, Yuan P, Zhang R, Ju FL, et al. (2012). BMPR2 mutations influence phenotype more obviously in male patients with pulmonary arterial hypertension. Circ Cardiovasc Genet, 5:511-518.
[29] Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, et al. (2006). Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat, 27:121-132.
[30] Spiekerkoetter E, Sung YK, Sudheendra D, Bill M, Aldred MA, van de Veerdonk MC, et al. (2015). Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension. Am J Respir Crit Care Med, 192:254-257.
[31] Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, et al. (2013). FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest, 123:3600-3613.
[32] Takeda Y, Miyamori I, Furukawa K, Inaba S, Mabuchi H (1999). Mechanisms of FK 506-induced hypertension in the rat. Hypertension, 33:130-136.
[33] Spiekerkoetter E, Sung YK, Sudheendra D, Scott V, Del Rosario P, Bill M, et al. (2017). Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. The European respiratory journal, 50:undefined.
[34] Kurosawa R, Satoh K, Kikuchi N, Kikuchi H, Saigusa D, Al-Mamun ME, et al. (2019). Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension-High-throughput Screening of 5,562 Compounds. Circ Res.
[35] Huertas A, Phan C, Bordenave J, Tu L, Thuillet R, Le Hiress M, et al. (2016). Regulatory T Cell Dysfunction in Idiopathic, Heritable and Connective Tissue-Associated Pulmonary Arterial Hypertension. Chest, 149:1482-1493.
[36] Meng X, Yang J, Dong M, Zhang K, Tu E, Gao Q, et al. (2016). Regulatory T cells in cardiovascular diseases. Nature reviews. Cardiology, 13:167-179.
[37] Tamosiuniene R, Manouvakhova O, Mesange P, Saito T, Qian J, Sanyal M, et al. (2018). Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension. Circulation research, 122:1689-1702.
[38] Pugliese SC, Poth JM, Fini MA, Olschewski A, El Kasmi KC, Stenmark KR (2015). The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol, 308:L229-252.
[39] Kuebler WM, Bonnet S, Tabuchi A (2018). Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover Conference Series). Pulm Circ, 8:2045893218757596.
[40] Edwards AL, Gunningham SP, Clare GC, Hayman MW, Smith M, Frampton CM, et al. (2013). Professional killer cell deficiencies and decreased survival in pulmonary arterial hypertension. Respirology, 18:1271-1277.
[41] Ormiston ML, Chang C, Long LL, Soon E, Jones D, Machado R, et al. (2012). Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension. Circulation, 126:1099-1109.
[42] Rabinovitch M, Guignabert C, Humbert M, Nicolls MR (2014). Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res, 115:165-175.
[43] Huertas A, Phan C, Bordenave J, Tu L, Thuillet R, Le Hiress M, et al. (2016). Regulatory T Cell Dysfunction in Idiopathic, Heritable and Connective Tissue-Associated Pulmonary Arterial Hypertension. Chest, 149:1482-1493.
[44] Tamosiuniene R, Tian W, Dhillon G, Wang L, Sung YK, Gera L, et al. (2011). Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res, 109:867-879.
[45] Abid S, Marcos E, Parpaleix A, Amsellem V, Breau M, Houssaini A, et al. (2019). CCR2/CCR5-Mediated Macrophage-Smooth Muscle Cell Crosstalk in Pulmonary Hypertension. The European respiratory journal, undefined:undefined.
[46] Salah SM, Meisenheimer JD, Rao R, Peda JD, Wallace DP, Foster D, et al. (2019). MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in the model of polycystic kidney disease. American journal of physiology. Renal physiology, 317:F343-F360.
[47] Yasuoka H, Shirai Y, Tamura Y, Takeuchi T, Kuwana M (2018). Predictors of Favorable Responses to Immunosuppressive Treatment in Pulmonary Arterial Hypertension Associated With Connective Tissue Disease. Circ J, 82:546-554.
[48] Sun F, Lei Y, Wu W, Guo L, Wang K, Chen Z, et al. (2019). Two distinct clinical phenotypes of pulmonary arterial hypertension secondary to systemic lupus erythematosus. Ann Rheum Dis, 78:148-150.
[49] Qian J, Li M, Zhao J, Wang Q, Tian Z, Zeng X (2018). Inflammation in SLE-PAH: good news or not? Annals of the Rheumatic Diseases: annrheumdis-2018-214605.
[50] Tamura Y, Phan C, Tu L, Le Hiress M, Thuillet R, Jutant EM, et al. (2018). Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Invest, 128:1956-1970.
[51] Pickworth J, Rothman A, Iremonger J, Casbolt H, Hopkinson K, Hickey PM, et al. (2017). Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling. Pulm Circ, 7:768-776.
[52] Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, et al. (2010). Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation, 122:920-927.
[53] Voelkel NF, Tuder RM, Bridges J, Arend WP (1994). Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol, 11:664-675.
[54] Furuya Y, Satoh T, Kuwana M (2010). Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol, 2010:720305.
[55] Sanayama Y, Ikeda K, Saito Y, Kagami S, Yamagata M, Furuta S, et al. (2014). Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray. Arthritis Rheumatol, 66:1421-1431.
[56] Pullamsetti SS, Seeger W, Savai R (2018). Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension. J Clin Invest, 128:1720-1723.
[57] Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, et al. (1995). Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med, 151:1628-1631.
[58] Parpaleix A, Amsellem V, Houssaini A, Abid S, Breau M, Marcos E, et al. (2016). Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension. Eur Respir J, 48:470-483.
[59] Trankle CR, Canada JM, Kadariya D, Markley R, De Chazal HM, Pinson J, et al. (2019). IL-1 Blockade Reduces Inflammation in Pulmonary Arterial Hypertension and Right Ventricular Failure: A Single-Arm, Open-Label, Phase IB/II Pilot Study. American Journal of Respiratory and Critical Care Medicine, 199:381-384.
[60] Van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, et al. (2017). Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail, 10.
[61] Hennigan S, Channick RN, Silverman GJ (2008). Rituximab treatment of pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report. Lupus, 17:754-756.
[62] Wang L, Liu J, Wang W, Qi X, Wang Y, Tian B, et al. (2019). Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of beta-catenin. Thorax, 74:564-578.
[63] Hurst LA, Dunmore BJ, Long L, Crosby A, Al-Lamki R, Deighton J, et al. (2017). TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. communications, 8:14079.
[64] Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009). An operational definition of epigenetics. Genes Dev, 23:781-783.
[65] Kim GH, Ryan JJ, Archer SL (2013). The role of redox signaling in epigenetics and cardiovascular disease. Antioxid Redox Signal, 18:1920-1936.
[66] Zhao L, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, et al. (2012). Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation, 126:455-467.
[67] Bogaard HJ, Mizuno S, Hussaini AA, Toldo S, Abbate A, Kraskauskas D, et al. (2011). Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. Am J Respir Crit Care Med, 183:1402-1410.
[68] Dai Z, Zhao YY (2019). BET in Pulmonary Arterial Hypertension: Exploration of BET Inhibitors to Reverse Vascular Remodeling. Am J Respir Crit Care Med.
[69] Van der Feen DE, Kurakula K, Tremblay E, Boucherat O, Bossers GP, Szulcek R, et al. (2019). Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med.
[70] Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM (2001). Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res, 88:E2-e11.
[71] Ranchoux B, Meloche J, Paulin R, Boucherat O, Provencher S, Bonnet S (2016). DNA Damage and Pulmonary Hypertension. Int J Mol Sci, 17.
[72] Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, et al. (2015). Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med, 192:219-228.
[73] Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, et al. (2014). Role for DNA damage signaling in pulmonary arterial hypertension. Circulation, 129:786-797.
[74] Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. (2010). Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest, 137:376-387.
[75] Lahm T, Albrecht M, Fisher AJ, Selej M, Patel NG, Brown JA, et al. (2012). 17beta-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. Am J Respir Crit Care Med, 185:965-980.
[76] Chen X, Austin ED, Talati M, Fessel JP, Farber-Eger EH, Brittain EL, et al. (2017). Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects. Eur Respir J, 50.
[77] Jacobs W, van de Veerdonk MC, Trip P, de Man F, Heymans MW, Marcus JT, et al. (2014). The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest, 145:1230-1236.
[78] Baird GL, Archer-Chicko C, Barr RG, Bluemke DA, Foderaro AE, Fritz JS, et al. (2018). Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension. Eur Respir J, 51.
[79] Ventetuolo CE, Baird GL, Barr RG, Bluemke DA, Fritz JS, Hill NS, et al. (2016). Higher Estradiol and Lower Dehydroepiandrosterone-Sulfate Levels Are Associated with Pulmonary Arterial Hypertension in Men. Am J Respir Crit Care Med, 193:1168-1175.
[80] Kawut SM, Lima JA, Barr RG, Chahal H, Jain A, Tandri H, et al. (2011). Sex and race differences in right ventricular structure and function: the multi-ethnic study of atherosclerosis-right ventricle study. Circulation, 123:2542-2551.
[81] Mair KM, Yang XD, Long L, White K, Wallace E, Ewart MA, et al. (2015). Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells. Am J Respir Crit Care Med, 191:693-703.
[82] Mair KM, Harvey KY, Henry AD, Hillyard DZ, Nilsen M, MacLean MR (2019). Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension. Eur Respir J, 53.
[83] Kawut SM, Archer-Chicko CL, DeMichele A, Fritz JS, Klinger JR, Ky B, et al. (2017). Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial. Am J Respir Crit Care Med, 195:360-368.
[84] Michelakis ED, Gurtu V, Webster L, Barnes G, Watson G, Howard L, et al. (2017). Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients. Science translational medicine, 9:undefined.
[85] Sutendra G, Michelakis ED (2014). The metabolic basis of pulmonary arterial hypertension. Cell Metab, 19:558-573.
[86] Zhou Q, Chen J, Rexius-Hall ML, Rehman J, Zhou G (2018). Alpha-enolase regulates the malignant phenotype of pulmonary artery smooth muscle cells via the AMPK-Akt pathway.%A Dai J. Nature communications, 9:3850.
[87] Hansmann G, Wagner RA, Schellong S, Perez VA, Urashima T, Wang L, et al. (2007). Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation, 115:1275-1284.
[88] Omura J, Satoh K, Kikuchi N, Satoh T, Kurosawa R, Nogi M, et al. (2016). Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice. Circulation research, 119:197-209.
[89] Dean A, Nilsen M, Loughlin L, Salt IP, MacLean MR (2016). Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition. Hypertension, 68:446-454.
[90] Goncharov DA, Goncharova EA, Tofovic SP, Hu J, Baust JJ, Pena AZ, et al. (2018). Metformin Therapy for Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction versus Pulmonary Arterial Hypertension. Am J Respir Crit Care Med, 198:681-684.
[91] Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, et al. (2016). SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. Circulation, 133:717-731.
[92] Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. (2005). Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest, 115:2811-2821.
[93] Ciuclan L, Hussey MJ, Burton V, Good R, Duggan N, Beach S, et al. (2013). Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. American journal of respiratory and critical care medicine, 187:78-89.
[94] Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, et al. (2013). Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation, 127:1128-1138.
[95] Frost AE, Barst RJ, Hoeper MM, Chang HJ, Frantz RP, Fukumoto Y, et al. (2015). Long-term safety and efficacy of imatinib in pulmonary arterial hypertension. J Heart Lung Transplant, 34:1366-1375.
[96] Ogawa A, Miyaji K, Matsubara H (2017). Efficacy and safety of long-term imatinib therapy for patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Respir Med, 131:215-219.
[97] Guignabert C, Phan C, Seferian A, Huertas A, Tu L, Thuillet R, et al. (2016). Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. The Journal of clinical investigation, 126:3207-3218.
[98] Hansen T, Galougahi KK, Celermajer D, Rasko N, Tang O, Bubb KJ, et al. (2016). Oxidative and nitrosative signalling in pulmonary arterial hypertension Implications for development of novel therapies. Pharmacology & Therapeutics, 165:50-62.
[99] MK C, SY C (2018). Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains. The Journal of clinical investigation, 128:3704-3715.
[100] Budas GR, Boehm M, Kojonazarov B, Viswanathan G, Tian X, Veeroju S, et al. (2018). ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine, 197:373-385.
[101] Eba S, Hoshikawa Y, Moriguchi T, Mitsuishi Y, Satoh H, Ishida K, et al. (2013). The nuclear factor erythroid 2-related factor 2 activator oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice. Am J Respir Cell Mol Biol, 49:324-333.
[102] Grzegorzewska AP, Seta F, Han R, Czajka CA, Makino K, Stawski L, et al. (2017). Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Scientific reports, 7:41605.
[103] Hutchinson M, Fox RJ, Miller DH, Phillips JT, Kita M, Havrdova E, et al. (2013). Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the CONFIRM study. J Neurol, 260:2286-2296.
[104] Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. (2012). Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med, 367:1087-1097.
[105] Lu HI, Huang TH, Sung PH, Chen YL, Chua S, Chai HY, et al. (2016). Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice. Acta Pharmacol Sin, 37:589-603.
[106] Cheng Y, Gong Y, Qian S, Mou Y, Li H, Chen X, et al. (2018). Identification of a Novel Hybridization from Isosorbide 5-Mononitrate and Bardoxolone Methyl with Dual Activities of Pulmonary Vasodilation and Vascular Remodeling Inhibition on Pulmonary Arterial Hypertension Rats. Journal of medicinal chemistry, 61:1474-1482.
[107] Hoeper MM, Benza RL, Corris P, de Perrot M, Fadel E, Keogh AM, et al. (2019). Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension. European Respiratory Journal, 53.
[108] Machuca TN, de Perrot M (2015). Mechanical Support for the Failing Right Ventricle in Patients With Precapillary Pulmonary Hypertension. Circulation, 132:526-536.
[109] Gu M, Shao NY, Sa S, Li D, Termglinchan V, Ameen M, et al. (2017). Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers. Cell Stem Cell, 20:490-504 e495.
[110] Granton J, Langleben D, Kutryk MB, Camack N, Galipeau J, Courtman DW, et al. (2015). Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial. Circ Res, 117:645-654.
[111] Abraham WT, Stevenson LW, Bourge RC, Lindenfeld JA, Bauman JG, Adamson PB (2016). Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomised trial. Lancet, 387:453-461.
[112] Tudorache I, Sommer W, Kuhn C, Wiesner O, Hadem J, Fuhner T, et al. (2015). Lung transplantation for severe pulmonary hypertension--awake extracorporeal membrane oxygenation for postoperative left ventricular remodelling. Transplantation, 99:451-458.
[113] Galie N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al. (2016). 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J, 37:67-119.
[114] Bhamra-Ariza P, Keogh AM, Muller DWM (2014). Percutaneous interventional therapies for the treatment of patients with severe pulmonary hypertension. J Am Coll Cardiol, 63:611-618.
[115] Chen SL, Zhang FF, Xu J, Xie DJ, Zhou L, Nguyen T, et al. (2013). Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension). J Am Coll Cardiol, 62:1092-1100.
[116] Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, et al. (2001). Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med, 345:325-334.
[117] Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X, et al. (2010). Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med, 181:851-861.
[118] Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, et al. (2004). Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax, 59:446-448.
[119] Graf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, et al. (2018). Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat Commun, 9:1416.
[120] Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, et al. (2013). A novel channelopathy in pulmonary arterial hypertension. N Engl J Med, 369:351-361.
[121] Montani D, Girerd B, Jais X, Levy M, Amar D, Savale L, et al. (2017). Clinical phenotypes and outcomes of heritable and sporadic pulmonary veno-occlusive disease: a population-based study. Lancet Respir Med, 5:125-134.
[122] Levy M, Eyries M, Szezepanski I, Ladouceur M, Nadaud S, Bonnet D, et al. (2016). Genetic analyses in a cohort of children with pulmonary hypertension. Eur Respir J, 48:1118-1126.
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