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Review

Novel Experimental Therapies for Treatment of Pulmonary Arterial Hypertension

Pages 817-857 | Published online: 17 Aug 2021

References

  • Rubin LJ. Pulmonary arterial hypertension. Proc Am Thorac Soc. 2006;3(1):111–115. PMID: 16493158. doi:10.1513/pats.200510-112JH
  • Galiè N, McLaughlin VV, Rubin LJ, et al. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J. 2019;53(1):1802148. PMID: 30552088. doi:10.1183/13993003.02148-2018
  • Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. PMID: 30545968. doi:10.1183/13993003.01913-2018
  • Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res. 2006;99(7):675–691. PMID: 17008597. doi:10.1161/01.RES.0000243584.45145.3f
  • Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(3):261–272. PMID: 22679007. doi:10.1164/rccm.201201-0164OC
  • Tuder RM, Archer SL, Dorfmüller P, et al. Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D4–D12. PMID: 24355640. doi:10.1016/j.jacc.2013.10.025
  • Humbert M, Montani D, Perros F, et al. Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension. Vascul Pharmacol. 2008;49:113–118. PMID: 18606248. doi:10.1016/j.vph.2008.06.003
  • Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Investig. 2012;122:4306–4313. PMID: 23202738. doi:10.1172/JCI60658
  • Cohen-Kaminsky S, Hautefort A, Price L, et al. Inflammation in pulmonary hypertension: what we know and what we could logically and safely target first. Drug Discov Today. 2014;19:1251–1256. PMID: 24747559. doi:10.1016/j.drudis.2014.04.007
  • Ryan J, Dasgupta A, Huston J, et al. Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med. 2015;93:229–242. PMID: 25672499. doi:10.1007/s00109-015-1263-5
  • Potus F, Ruffenach G, Dahou A, et al. Downregulation of MicroRNA-126 contributes to the failing right ventricle in pulmonary arterial hypertension. Circulation. 2015;132:932–943. PMID: 26162916. doi:10.1161/CIRCULATIONAHA.115.016382
  • Potus F, Malenfant S, Graydon C, et al. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014;190:318–328. PMID: 2497762. doi:10.1164/rccm.201402-0383OC
  • Ranchoux B, Antigny F, Rucker-Martin C, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation. 2015;131:1006–1018. PMID: 25593290. doi:10.1161/CIRCULATIONAHA.114.008750
  • Kherbeck N, Tamby MC, Bussone G, et al. The role of inflammation and autoimmunity in the pathophysiology of pulmonary arterial hypertension. Clin Rev Allergy Immunol. 2013;44:31–38. PMID: 21394427. doi:10.1007/s12016-011-8265-z
  • Malenfant S, Neyron AS, Paulin R, et al. Signal transduction in the development of pulmonary arterial hypertension. Pulm Circ. 2013;3:278–293. PMID: 24015329. doi:10.4103/2045-8932.114752
  • Perros F, Humbert M, Cohen-Kaminsky S. Pulmonary arterial hypertension: a flavor of autoimmunity. Méd Sci. 2013;29:607–616. PMID: 23859515. doi:10.1051/medsci/2013296013.12
  • Montani D, Günther S, Dorfmüller P, et al. Pulmonary arterial hypertension. Orphanet J Rare Dis. 2013;8:97. PMID: 23829793. doi:10.1186/1750-1172-8-97
  • Toshner M, Tajsic T, Morrell NW. Pulmonary hypertension: advances in pathogenesis and treatment. Br Med Bull. 2010;94:21–32. PMID: 20447940. doi:10.1093/bmb/ldq012
  • Morrell NW, Adnot S, Archer SL, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1Suppl):S20–31. PMID: 19555855. doi:10.1016/j.jacc.2009.04.018
  • Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation. 1970;42:1163–1184. doi:10.1161/01.CIR.42.6.1163
  • Caruso P, Dunmore BJ, Schlosser K, et al. Identification of MicroRNA‐124 as a major regulator of enhanced endothelial cell glycolysis in pulmonary arterial hypertension via PTBP1 (polypyrimidine tract binding protein) and pyruvate kinase M2. Circulation. 2017;136:2451–2467. PMID: 28971999. doi:10.1161/CIRCULATIONAHA.117.028034
  • Lane KB, Machado RD, Pauciulo MW, et al.; Consortium IP. Heterozygous germline mutations in BMPR2, encoding a TGF‐beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81–84. PMID: 10973254. doi:10.1038/79226
  • Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010;121:2045–2066. PMID: 20458021. doi:10.1161/CIRCULATIONAHA.108.847707
  • Landsberg JW, Yuan JX. Calcium and TRP channels in pulmonary vascular smooth muscle cell proliferation. News Physiol Sci. 2004;19:44–50. PMID: 15016901. doi:10.1152/nips.01457.2003
  • Archer SL. Pyruvate kinase and Warburg metabolism in pulmonary arterial hypertension: uncoupled glycolysis and the cancer‐like phenotype of pulmonary arterial hypertension. Circulation. 2017;136:2486–2490. PMID: 29255124. doi:10.1161/CIRCULATIONAHA.117.031655
  • Zhang H, Wang D, Li M, et al. Metabolic and proliferative state of vascular adventitial fibroblasts in pulmonary hypertension is regulated through a MicroRNA‐124/PTBP1 (polypyrimidine tract binding protein 1)/pyruvate kinase muscle axis. Circulation. 2017;136:2468–2485. PMID: 28972001 F. doi:10.1161/CIRCULATIONAHA.117.028069
  • Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res. 2014;115:165–175. PMID: 24951765. doi:10.1161/CIRCRESAHA.113.301141
  • Galiè N, Humbert M, Vachiery JL, et al.; ESC Scientific Document Group. 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. 2016;37:67–119. PMID: 26320113. doi:10.1093/eurheartj/ehv317
  • Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122(2):156–163. PMID: 20585011. doi:10.1161/CIRCULATIONAHA.109.911818
  • Fujii M, Takeda K, Imamura T, et al. Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation. Mol Biol Cell. 1999;10(11):3801–3813. PMID: 10564272. doi:10.1091/mbc.10.11.3801
  • Miyazono K, Maeda S, Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev. 2005;16(3):251–263. PMID: 15871923. doi:10.1016/j.cytogfr.2005.01.009
  • Machado RD, Eickelberg O, Elliott CG, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(1Suppl):S32–42. PMID: 19555857. doi:10.1016/j.jacc.2009.04.015
  • Valdimarsdottir G, Goumans MJ, Rosendahl A, et al. Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation. 2002;106(17):2263–2270. PMID: 12390958. doi:10.1161/01.cir.0000033830.36431.46
  • Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res. 2006;98(2):209–217. PMID: 16357305. doi:10.1161/01.RES.0000200180.01710.e6
  • Soon E, Crosby A, Southwood M, et al. Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(7):859–872. PMID: 26073741. doi:10.1164/rccm.201408-1509OC18
  • de Jesus Perez VA, Alastalo T-P, Wu JC, et al. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J Cell Biol. 2009;184(1):83–99. PMID: 19139264. doi:10.1083/jcb.200806049
  • Hansmann G, de Jesus Perez VA, Alastalo TP, et al. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest. 2008;118:1846–1857. PMID: 18382765. doi:10.1172/jci32503
  • Kawabata M, Imamura T, Miyazono K. Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev. 1998;9(1):49–61. PMID: 9720756. doi:10.1016/s1359-6101(97)00036-1
  • Massagué J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000;14(6):627–644. PMID: 10733523.
  • Attisano L, Wrana J. Signal transduction by the TGF-beta superfamily. Science. 2002;296(5573):1646–1647. PMID: 12040180. doi:10.1126/science.1071809
  • Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67(3):737–744. PMID: 10903931. doi:10.1086/303059
  • Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet. 2000;37:741–745. PMID: 11015450. doi:10.1136/jmg.37.10.741
  • Atkinson C, Stewart S, Upton PD, et al. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105(14):1672–1678. PMID: 11940546. doi:10.1161/01.CIR.0000012754.72951.3D
  • Austin ED, Hamid R, Hemnes AR, et al. BMPR2 expression is suppressed by signaling through the estrogen receptor. Biol Sex Differ. 2012;3(1):6. PMID: 22348410. doi:10.1186/2042-6410-3-6
  • West J, Fagan K, Steudel W, et al. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res. 2004;94(8):1109–1114. PMID: 15031260. doi:10.1161/01.RES.0000126047.82846.20
  • Hong KH, Lee YJ, Lee E, et al. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension. Circulation. 2008;118(7):722–730. PMID: 18663089. doi:10.1161/CIRCULATIONAHA.107.736801
  • Morrell NW, Yang X, Upton PD, et al. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation. 2001;104:790–795. PMID: 11502704. doi:10.1161/hc3201.094152
  • Fung JJ. Tacrolimus and transplantation: a decade in review. Transplantation. 2004;77(9):S41–S43. PMID: 15201685. doi:10.1097/01.tp.0000126926.61434.a5
  • Spiekerkoetter E, Tian X, Cai J, et al. FK506 activates BMPR-II, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest. 2013;123:3600–3613. PMID: 23867624. doi:10.1172/JCI65592
  • Spiekerkoetter E, Sung YK, Sudheendra D, et al. Low-dose FK506 (tacrolimus) in end-stage pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;192(2):254–257. PMID: 26177174. doi:10.1164/rccm.201411-2061LE
  • Spiekerkoetter E, Sung YK, Sudheendra D, et al. Randomised placebo controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J. 2017;50:1602449. PMID: 28893866. doi:10.1183/13993003.02449-2016
  • Al‐Bari MA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother. 2015;70:1608–1621. PMID: 25693996. doi:10.1093/jac/dkv018
  • Long L, Yang X, Southwood M, et al. Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type ii receptor degradation. Circ Res. 2013;112(8):1159–1170. PMID: 23446737. doi:10.1161/CIRCRESAHA.111.300483
  • Humbert M, McLaughlin V, Gibbs JSR, et al.; PULSAR Trial Investigators. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med. 2021;384(13):1204–1215. PMID: 33789009. doi:10.1056/NEJMoa2024277
  • Goldenberg NM, Steinberg BE. Inflammation drives pulmonary arterial hypertension. Anesthesiology. 2019;130(5):820–821. PMID: 30994559. doi:10.1097/ALN.0000000000002561
  • Mouthon L, Guillevin L, Humbert M. Pulmonary arterial hypertension: an autoimmune disease? Eur Respir J. 2005;26:986–988. PMID: 16319325. doi:10.1183/09031936.05.00112105
  • Nicolls MR, Taraseviciene-Stewart L, Rai PR, et al. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J. 2005;26:1110–1118. PMID: 16319344. doi:10.1183/09031936.05.00045705
  • Rabinovitch M. Autoimmune disease and unexplained pulmonary hypertension. Circulation. 1992;85:380–381. PMID: 1728476. doi:10.1161/01.cir.85.1.380
  • Perros F, Dorfmuller P, Montani D, et al. Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185:311–321. PMID: 22108206. doi:10.1164/rccm.201105-0927OC
  • Dorfmuller P, Perros F, Balabanian K, et al. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003;22:358–363. PMID: 12952274. doi:10.1183/09031936.03.00038903
  • Blum LK, Cao RRL, Sweatt AJ, et al. Circulating plasmablasts are elevated and produce pathogenic anti-endothelial cell autoantibodies in idiopathic pulmonary arterial hypertension. Eur J Immunol. 2018;48:874–884. PMID: 29369345. doi:10.1002/eji.201747460
  • de Bourcy CFA, Dekker CL, Davis MM, et al. Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis. Sci Immunol. 2017;2(15):eaan8289. PMID: 28963118. doi:10.1126/sciimmunol.aan8289
  • Huertas A, Phan C, Bordenave J, et al. Regulatory T cell dysfunction in idiopathic, heritable and connective tissue-associated pulmonary arterial hypertension. Chest. 2016;149:1482–1493. PMID: 26836928. doi:10.1016/j.chest.2016.01.004
  • Hautefort A, Girerd B, Montani D, et al. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest. 2015;147:1610–1620. PMID: 25429518. doi:10.1378/chest.14-1678
  • Savai R, Pullamsetti SS, Kolbe J, et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:897–908. PMID: 22955318. doi:10.1164/rccm.201202-0335OC
  • Klinke A, Berghausen E, Friedrichs K, et al. Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase. JCI Insight. 2018;3(11):e97530. PMID: 29875311. doi:10.1172/jci.insight.97530
  • Harbaum L, Baaske KM, Simon M, et al. Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension. BMC Pulm Med. 2017;17(1):72. PMID: 28446163. doi:10.1186/s12890-017-0407-5
  • Taylor S, Dirir O, Zamanian RT, et al. The role of neutrophils and neutrophil elastase in pulmonary arterial hypertension. Front Med (Lausanne). 2018;5:217. PMID: 30131961. doi:10.3389/fmed.2018.00217
  • Marsh LM, Jandl K, Grünig G, et al. The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2018;51(1):1701214. PMID: 29371380. doi:10.1183/13993003.01214-2017
  • Cracowski JL, Chabot F, Labarere J, et al. Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension. Eur Respir J. 2014;43:915–917. PMID: 24232704. doi:10.1183/16000617.0084-2016387
  • Molossi S, Clausell N, Rabinovitch M. Reciprocal induction of tumor necrosis factor-alpha and interleukin-1 beta activity mediates fibronectin synthesis in coronary artery smooth muscle cells. J Cell Physiol. 1995;163:19–29. PMID: 7896895. doi:10.1002/jcp.1041630104
  • Jones PL, Cowan KN, Rabinovitch M. Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol. 1997;150:1349–1360. PMID: 9094991.
  • Courboulin A, Tremblay VL, Barrier M, et al. Krüppel-like factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension. Respir Res. 2011;12:128. PMID: 21951574F. doi:10.1186/1465-9921-12-128
  • Frid MG, Brunetti JA, Burke DL, et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol. 2006;168:659–669. PMID: 16436679. doi:10.2353/ajpath.2006.050599
  • Ito T, Okada T, Miyashita H, et al. Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. Circ Res. 2007;101:734–741. PMID: 17673672. doi:10.1161/CIRCRESAHA.107.153023
  • Miyamichi-Yamamoto S, Fukumoto Y, Sugimura K, et al. Intensive immunosuppressive therapy improves pulmonary hemodynamics and long-term prognosis in patients with pulmonary arterial hypertension associated with connective tissue disease. Circ J. 2011;75:2668–2674. PMID: 21873802. doi:10.1253/circj.cj-11-0473
  • Kommireddy S, Bhyravavajhala S, Kurimeti K, et al. Pulmonary arterial hypertension in systemic lupus erythematosus may benefit by addition of immunosuppression to vasodilator therapy: an observational study. Rheumatology (Oxford). 2015;54:1673–1679. PMID: 25929760. doi:10.1093/rheumatology/kev097
  • Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, et al. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med. 2007;175:1280–1289. PMID: 17413127. doi:10.1164/rccm.200608-1189OC
  • Steiner MK, Syrkina OL, Kolliputi N, et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res. 2009;104:236–244. PMID: 19074475. doi:10.1161/CIRCRESAHA.108.182014
  • Savale L, Tu L, Rideau D, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res. 2009;10(1):6. PMID: 19173740. doi:10.1186/1465-9921-10-6
  • Tamura Y, Phan C, Tu L, et al. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J Clin Investig. 2018;128:1956–1970. PMID: 29629897. doi:10.1172/JCI96462
  • Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;151:1628–1631. PMID: 7735624. doi:10.1164/ajrccm.151.5.7735624
  • Soon E, Holmes AM, Treacy CM, et al. Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation. 2010;122:920–927. PMID: 20713898. doi:10.1161/CIRCULATIONAHA.109.933762
  • Taniguchi K, Shimazaki C, Fujimoto Y, et al. Tocilizumab is effective for pulmonary hypertension associated with multicentric Castleman’s disease. Int J Hematol. 2009;90(1):99–102. PMID: 19554396. doi:10.1007/s12185-009-0346-x
  • Arita Y, Sakata Y, Sudo T, et al. The efficacy of tocilizumab in a patient with pulmonary arterial hypertension associated with Castleman’s disease. Heart Vessels. 2010;25(5):444–447. PMID: 20676969. doi:10.1007/s00380-009-1215-5
  • Kadavath S, Zapantis E, Zolty R, et al. A novel therapeutic approach in pulmonary arterial hypertension as a complication of adult-onset Still’s disease: targeting IL-6. Int J Rheum Dis. 2014;17(3):336–340. PMID: 24581387. doi:10.1111/1756-185X.12324
  • Voelkel NF, Tuder RM, Bridges J, Arend WP. Interleukin‐1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. Am J Respir Cell Mol Biol. 1994;11:664–675. PMID: 7946395. doi:10.1165/ajrcmb.11.6.7946395
  • Voelkel NF, Tuder R. Interleukin-1 receptor antagonist inhibits pulmonary hypertension induced by inflammation. Ann N Y Acad Sci. 1994;725:104–109. PMID: 8030981. doi:10.1111/j.1749-6632.1994.tb39794.x
  • Pickworth J, Rothman A, Iremonger J, et al. Differential IL‐1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling. Pulm Circ. 2017;7:768–776. PMID: 28828907. doi:10.1177/2045893217729096
  • Mertens M, Singh JA. Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol. 2009;36:1118–1125. PMID: 19447938. doi:10.3899/jrheum.090074
  • Trankle CR, Canada JM, Kadariya D, et al. Interleukin‐1 (IL‐1) blockade reduces inflammation in pulmonary arterial hypertension and right ventricular failure: a single‐arm, open‐label, phase IB/II pilot study. Am J Respir Crit Care Med. 2019;199(3):381–384. PMID: 30418047. doi:10.1164/rccm.201809-1631LE
  • Zhang LL, Lu J, Li MT, et al. Preventive and remedial application of etanercept attenuate monocrotaline‐induced pulmonary arterial hypertension. Int J Rheum Dis. 2016;19:192–198. PMID: 24612527. doi:10.1111/1756-185X.12304
  • Fujita M, Shannon JM, Irvin CG, et al. Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2001;280(1):L39–49. PMID: 11133493. doi:10.1152/ajplung.2001.280.1.L39
  • Li XQ, Wang HM, Yang CG, et al. Fluoxetine inhibited extracellular matrix of pulmonary artery and inflammation of lungs in monocrotaline-treated rats. Acta Pharmacol Sin. 2011;32(2):217–222. PMID: 21217769. doi:10.1038/aps.2010.187
  • Chen D, Zhou D, Qian J, et al. Atorvastatin prevents dehydromonocrotaline-induced pulmonary hypertension in beagles. Exp Lung Res. 2012;38(7):333–343. PMID: 22888849. doi:10.3109/01902148.2012.702852
  • Hurst LA, Dunmore BJ, Long L, et al. TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling. Nat Commun. 2017;8:14079. PMID: 28084316. doi:10.1038/ncomms14079
  • Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: FC fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340:253–259. PMID: 9920948. doi:10.1056/NEJM199901283400401
  • Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999;130:478–486. PMID: 10075615. doi:10.7326/0003-4819-130-6-199903160-00004
  • Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta‐analysis. Am J Gastroenterol. 2011;106:644–659. PMID: 21407183. doi:10.1038/ajg.2011.73
  • Mease PJ. Tumor necrosis factor (TNF) in psoriatic arthritis: pathophysiology and treatment with TNF inhibitors. Ann Rheum Dis. 2002;61:298–304. PMID: 11874829. doi:10.1136/ard.61.4.298
  • Mutschler D, Wikström G, Lind L, et al. Etanercept reduces late endotoxin-induced pulmonary hypertension in the pig. J Interferon Cytokine Res. 2006;26(9):661–667. PMID: 16978070. doi:10.1089/jir.2006.26.661
  • Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell. 2017;168:37–57. PMID: 28086098. doi:10.1016/j.cell.2016.12.012
  • Sawada H, Mitani Y, Maruyama J, et al. A nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate ameliorates pulmonary hypertension in rats. Chest. 2007;132:1265–1274. PMID: 17934115. doi:10.1378/chest.06-2243
  • Price LC, Caramori G, Perros F, et al. Nuclear factor κ-B is activated in the pulmonary vessels of patients with end-stage idiopathic pulmonary arterial hypertension. PLoS One. 2013;8(10):e75415. PMID: 24124488. doi:10.1371/journal.pone.0075415
  • Chin MP, Bakris GL, Block GA, et al. Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes: post-hoc analyses from bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study. Am J Nephrol. 2018;47:40–47. PMID: 29402767. doi:10.1159/000486398
  • Oudiz R, Meyer C, Chin M, et al. Initial data report from “LARIAT”: a phase 2 study of bardoxolone methyl in PAH patients on stable background therapy. Chest. 2015;148:639 A. doi:10.1378/chest.2345856
  • Grzegorzewska AP, Seta F, Han R, et al. Dimethyl fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep. 2017;7:41605. PMID: 28150703. doi:10.1038/srep41605
  • Zhao G, Liu Y, Fang J, et al. Dimethyl fumarate inhibits the expression and function of hypoxia-inducible factor-1α (HIF-1α). Biochem Biophys Res Commun. 2014;448:303–307. PMID: 24569076. doi:10.1016/j.bbrc.2014.02.062
  • Bosch X, Ramos-Casals M, Khamashta MA. Drugs Targeting B-Cells in Autoimmune Diseases. Springer Science & Business Media; 2013:1–4.
  • Nicolls M, Badesch D, Chung L, et al.; ASC01 Investigators. Safety and efficacy of B-cell depletion with rituximab for the treatment of systemic sclerosis-associated pulmonary arterial hypertension in a multi-center NIH Clinical Trial. Arthritis Rheumatol. 2019;71(S10):Abstract 0867.
  • Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54:S10–19. PMID: 19555853. doi:10.1016/j.jacc.2009.04.006
  • Perros F, Montani D, Dorfmuller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:81–88. PMID: 18420966. doi:10.1164/rccm.200707-1037OC
  • Medarametla V, Festin S, Sugarragchaa C, et al. PK10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension. Pulm Circ. 2014;4(1):82–102. PMID: 25006424. doi:10.1086/674881
  • Klein M, Schermuly RT, Ellinghaus P, et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation. 2008;118(20):2081–2090. PMID: 18955668. doi:10.1161/CIRCULATIONAHA.108.779751
  • Redner RL. Why doesn’t imatinib cure chronic myeloid leukemia? Oncologist. 2010;15(2):182–186. PMID: 20124443. doi:10.1634/theoncologist.2009-0297
  • Dagher R, Cohen M, Williams G. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002;8:3034–3038. PMID: 12374669.
  • Schermuly RT, Dony E, Ghofrani HA, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115(10):2811–2821. PMID: 16200212. doi:10.1172/JCI24838
  • Patterson KC, Weissmann A, Ahmadi T, et al. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. 2006;145(2):152–153. PMID: 16847299. doi:10.7326/0003-4819-145-2-200607180-00020
  • ten Freyhaus H, Dumitrescu D, Berghausen E, et al. Imatinib mesylate for the treatment of pulmonary arterial hypertension. Expert Opin Investig Drugs. 2012;21(1):119–134. PMID: 22074410. doi:10.1517/13543784.2012.632408
  • Ghofrani HA, Morrell NW, Hoeper MM, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med. 2010;182(9):1171–1177. PMID: 20581169. doi:10.1164/rccm.201001-0123OC
  • Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013;127(10):1128–1138. PMID: 23403476. doi:10.1161/CIRCULATIONAHA.112.000765
  • Shah AM, Campbell P, Rocha GQ, et al. Effect of imatinib as add-on therapy on echocardiographic measures of right ventricular function in patients with significant pulmonary arterial hypertension. Eur Heart J. 2015;36(10):623–632. PMID: 24566799. doi:10.1093/eurheartj/ehu035
  • Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–134. PMID: 17215530. doi:10.1056/NEJMoa060655
  • Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390. PMID: 18650514. doi:10.1056/NEJMoa0708857
  • Man CH, Fung TK, Ho C, et al. Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood. 2012;119(22):5133–5143. PMID: 22368270. doi:10.1182/blood-2011-06-363960
  • Worden F. Treatment strategies for radioactive iodine refractory differentiated thyroid cancer. Ther Adv Med Oncol. 2014;6(6):267–279. PMID: 25364392. doi:10.1177/1758834014548188
  • Ranieri G, Gadaleta-Caldarola G, Goffredo V, et al. Sorafenib (BAY 43-9006) in hepatocellular carcinoma patients: from discovery to clinical development. Curr Med Chem. 2012;19(7):938–944. PMID: 22214462. doi:10.2174/092986712799320736
  • Moreno-Vinasco L, Gomberg-Maitland M, Maitland ML, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics. 2008;33(2):278–291. PMID: 18303084. doi:10.1152/physiolgenomics.00169.2007
  • Kimura G, Kataoka M, Inami T, et al. Sorafenib as a potential strategy for refractory pulmonary arterial hypertension. Pulm Pharmacol Ther. 2017;44:46–49. PMID: 28315488. doi:10.1016/j.pupt.2017.03.009
  • Gomberg-Maitland M, Maitland ML, Barst RJ, et al. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2010;87(3):303–310. PMID: 20010555. doi:10.1038/clpt.2009.217
  • Manley P, Cowan-Jacob S, Mestan J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim Biophys Acta. 2005;1754(1–2):3–13. PMID: 16172030. doi:10.1016/j.bbapap.2005.07.040
  • Jabbour E, Cortes J, Kantarjian H. Nilotinib for the treatment of chronic myeloid leukemia: an evidence-based review. Core Evid. 2010;4:207–213. PMID: 20694077. doi:10.2147/ce.s6003
  • Olivieri A, Manzione L. Dasatinib: a new step in molecular target therapy. Ann Oncol. 2007;18(Suppl 6):vi42–6. PMID: 17591830. doi:10.1093/annonc/mdm223
  • Breccia M, Alimena G. Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia. Leuk Res. 2010;34(2):129–134. PMID: 19783301. doi:10.1016/j.leukres.2009.08.031
  • Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542–2551. PMID: 16775235. doi:10.1056/NEJMoa055104
  • Keating GM. Dasatinib: a review in chronic myeloid leukaemia and Ph+ acute lymphoblastic leukaemia. Drugs. 2017;77(1):85–96. PMID: 28032244. doi:10.1007/s40265-016-0677-x
  • Dumitrescu D, Seck C, ten Freyhaus H, et al. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J. 2011;38(1):218–220. PMID: 21719499. doi:10.1183/09031936.00154210
  • Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125(17):2128–2137. PMID: 22451584. doi:10.1161/CIRCULATIONAHA.111.079921
  • Wang Y, Zheng XR, Riddick N, et al. ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res. 2009;104(4):531–540. PMID: 19131646. doi:10.1161/CIRCRESAHA.108.188524
  • Fagan KA, Oka M, Bauer NR, et al. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol. 2004;287:L656–L664. PMID: 14977625. doi:10.1152/ajplung.00090.2003
  • Loirand G, Guérin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res. 2006;98(3):322–334. PMID: 16484628. doi:10.1161/01.RES.0000201960.04223.3c
  • Nagaoka T, Morio Y, Casanova N, et al. Rho/Rho kinase signaling mediates increased basal pulmonary vascular tone in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol. 2004;287(4):L665–72. PMID: 12959926. doi:10.1152/ajplung.00050.2003
  • Walker J, Undem C, Yun X, Lade J, Jiang H, Shimoda LA. Role of Rho kinase and Na+/H+ exchange in hypoxia-induced pulmonary arterial smooth muscle cell proliferation and migration. Physiol Rep. 2016;4(6):e12702. PMID: 27009277. doi:10.14814/phy2.12702
  • Madden JA, Ray DE, Keller PA, Kleinman JG. Ion exchange activity in pulmonary artery smooth muscle cells: the response to hypoxia. Am J Physiol Lung Cell Mol Physiol. 2001;280(2):L264–71. PMID: 11159005. doi:10.1152/ajplung.2001.280.2.L264
  • McMurtry IF, Bauer NR, Fagan KA, Nagaoka T, Gebb SA, Oka M. Hypoxia and Rho/Rho-kinase signaling. Lung development versus hypoxic pulmonary hypertension. Adv Exp Med Biol. 2003;543:127–137. PMID: 14713118.
  • Wojciak-Stothard B, Tsang LY, Haworth SG. Rac and Rho play opposing roles in the regulation of hypoxia/reoxygenation-induced permeability changes in pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2005;288:L749–L760. PMID: 15591411. doi:10.1152/ajplung.00361.2004
  • Guilluy C, Eddahibi S, Agard C, et al. RhoA and Rho kinase activation in human pulmonary hypertension: role of 5-HT signaling. Am J Respir Crit Care Med. 2009;179(12):1151–1158. PMID: 19299501. doi:10.1164/rccm.200805-691OC
  • Shimokawa H, Hiramori K, Iinuma H, et al. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol. 2002;40(5):751–761. PMID: 12409984. doi:10.1097/00005344-200211000-00013
  • Tachibana E, Harada T, Shibuya M, et al. Intra-arterial infusion of fasudil hydrochloride for treating vasospasm following subarachnoid haemorrhage. Acta Neurochir (Wien). 1999;141(1):13–19. PMID: 10071681. doi:10.1007/s007010050260
  • Somlyo AP, Somlyo AV. Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol. 2000;522(Pt 2):177–185. PMID: 10639096. doi:10.1111/j.1469-7793.2000.t01-2-00177.x
  • Fukumoto Y, Matoba T, Ito A, et al. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart. 2005;91(3):391–392. PMID: 15710736. doi:10.1136/hrt.2003.029470
  • Fukumoto Y, Yamada N, Matsubara H, et al. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J. 2013;77(10):2619–2625. PMID: 23912836. doi:10.1253/circj.cj-13-0443
  • Liu AJ, Ling F, Wang D, et al. Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip1 via the ERK signal pathway. Chin Med J (Engl). 2011;124(19):3098–3104. PMID: 22040563.
  • Fujita H, Fukumoto Y, Saji K, et al. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels. 2010;25(2):144–149. PMID: 20339976. doi:10.1007/s00380-009-1176-8
  • 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(1):144–152. PMID: 23662191. doi:10.4103/2045-8932.109960
  • Archer SL, Marsboom G, Kim GH, et al. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121(24):2661–2671. PMID: 20529999F. doi:10.1161/CIRCULATIONAHA.109.916098
  • Sutendra G, Michelakis ED. The metabolic basis of pulmonary arterial hypertension. Cell Metab. 2014;19:558‐ 573. PMID: 24508506. doi:10.1016/j.cmet.2014.01.004
  • Ryan JJ, Archer SL. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part I: metabolic plasticity and mitochondrial dynamics in the pulmonary circulation and right ventricle in pulmonary arterial hypertension. Circulation. 2015;131:1691‐ 1702. PMID: 25964279. doi:10.1161/CIRCULATIONAHA.114.006979
  • Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. Eur Respir Rev. 2012;21:19–26. PMID: 22379170. doi:10.1183/09059180.00008411
  • Warburg O. On the origin of cancer cells. Science. 1956;123:309‐ 314. PMID: 13298683. doi:10.1126/science.123.3191.309
  • Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension. Circ Res. 2014;115:148–164. PMID: 24951764. doi:10.1161/CIRCRESAHA.115.301130.
  • Michelakis ED, McMurtry MS, Wu XC, et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation. 2002;105:244–250. PMID: 11790708. doi:10.1161/hc0202.101974
  • McMurtry MS, Bonnet S, Wu X, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004;95:830–840. PMID: 15375007. doi:10.1161/01.RES.0000145360.16770.9f
  • Piao L, Sidhu VK, Fang YH, et al. FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate. J Mol Med (Berl). 2013;91:333–346. PMID: 23247844. doi:10.1007/s00109-012-0982-0
  • Michelakis ED, Gurtu V, Webster L, et al. Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients. Sci Transl Med. 2017;9(413):pii: eaao4583. PMID: 29070699. doi:10.1126/scitranslmed.aao4583
  • Nelson CH, Etchevers K, Yi S, et al. Pharmacokinetics, safety, and tolerability of selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, following first-in-human single and multiple ascending doses in healthy subjects. Clin Pharmacokinet. 2020;59(9):1109–1117. PMID: 32333325. doi:10.1007/s40262-020-00878-y
  • Hawwa N, Menon V. Ranolazine: clinical applications and therapeutic basis. Am J Cardiovasc Drugs. 2013;13(1):5–16. PMID: 23335347. doi:10.1007/s40256-012-0003-2
  • Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–1382. PMID: 15093870. doi:10.1016/j.jacc.2003.11.045
  • Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004;291:309–316. PMID: 14734593. doi:10.1001/jama.291.3.309
  • Hasenfuss G, Maier LS. Mechanism of action of the new anti-ischemia drug ranolazine. Clin Res Cardiol. 2008;97:222–226. PMID: 18046526. doi:10.1007/s00392-007-0612-y
  • Fang YH, Piao L, Hong Z, et al. Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle’s cycle. J Mol Med. 2012;90:31–43. PMID: 21874543. doi:10.1007/s00109-011-0804-9
  • Gomberg-Maitland M, Schilz R, Mediratta A, et al. Phase I safety study of ranolazine in pulmonary arterial hypertension. Pulm Circ. 2015;5:691–700. PMID: 26697176. doi:10.1086/683813
  • Khan SS, Cuttica MJ, Beussink-Nelson L, et al. Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study. Pulm Circ. 2015;5(3):547–556. PMID: 26401256. doi:10.1086/682427
  • Han Y, Forfia PR, Vaidya A, et al. Rationale and design of the ranolazine PH-RV study: a multicentred randomised and placebo-controlled study of ranolazine to improve RV function in patients with non-group 2 pulmonary hypertension. Open Heart. 2018;5(1):e000736. PMID: 29531764. doi:10.1136/openhrt-2017-000736
  • Sutendra G, Bonnet S, Rochefort G, et al. Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med. 2010;2(44):44–58. PMID: 20702857. doi:10.1126/scitranslmed.3001327
  • Aggarwal S, Gross CM, Sharma S, et al. Reactive oxygen species in pulmonary vascular remodeling. Compr Physiol. 2013;3:1011–1034. PMID: 23897679. doi:10.1002/cphy.c120024
  • Fulton D, Li X, Bordan Z, et al. Reactive oxygen and nitrogen species in the development of pulmonary hypertension. Antioxidants (Basel). 2017;6(3):54. PMID: 28684719. doi:10.3390/antiox6030054
  • Jernigan NL, Naik JS, Weise-Cross L, et al. Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension. PLoS One. 2017;12(6):e0180455. PMID: 28666030. doi:10.1371/journal.pone.0180455
  • Zuo L, Rose BA, Roberts WJ, et al. Molecular characterization of reactive oxygen species in systemic and pulmonary hypertension. Am J Hypertens. 2014;27(5):643–650. PMID: 24552887. doi:10.1093/ajh/hpt292
  • Anwar A, Ruffenach G, Mahajan A, et al. Novel biomarkers for pulmonary arterial hypertension. Respir Res. 2016;17(1):88. PMID: 27439993. doi:10.1186/s12931-016-0396-6
  • Reis GS, Augusto VS, Silveira APC, et al. Oxidative-stress biomarkers in patients with pulmonary hypertension. Pulm Circ. 2013;3(4):856–861. PMID: 25006401. doi:10.1086/674764
  • Zhang S, Yang T, Xu X, et al. Oxidative stress and nitric oxide signaling related biomarkers in patients with pulmonary hypertension: a case control study. BMC Pulm Med. 2015;15:50. PMID: 25934483. doi:10.1186/s12890-015-0045-8
  • Beckman JS, Beckman TW, Chen J, et al. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990;87(4):1620–1624. PMID: 2154753. doi:10.1073/pnas.87.4.1620
  • Chen CA, Wang TY, Varadharaj S, et al. S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature. 2010;468(7327):1115–1118. PMID: 21179168. doi:10.1038/nature09599
  • Elahi MM, Kong YX, Matata BM. Oxidative stress as a mediator of cardiovascular disease. Oxid Med Cell Longev. 2009;2(5):259–269. PMID: 20716913. doi:10.4161/oxim.2.5.9441
  • Bowers R, Cool C, Murphy RC, et al. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med. 2004;169:764–769. PMID: 14701708. doi:10.1164/rccm.200301-147OC
  • Demarco VG, Whaley-Connell AT, Sowers JR, et al. Contribution of oxidative stress to pulmonary arterial hypertension. World J Cardiol. 2010;2:316–324. PMID: 21160609. doi:10.4330/wjc.v2.i10.316
  • Dorfmüller P, Chaumais M-C, Giannakouli M, et al. Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension. Respir Res. 2011;12:119. PMID: 21906276. doi:10.1186/1465-9921-12-119
  • Black SM, DeVol JM, Wedgwood S. Regulation of fibroblast growth factor-2 expression in pulmonary arterial smooth muscle cells involves increased reactive oxygen species generation. Am J Physiol Cell Physiol. 2008;294:C345–C354. PMID: 17942638. doi:10.1152/ajpcell.00216.2007
  • Montisano DF, Mann T, Spragg RG. H2O2 increases expression of pulmonary artery endothelial cell platelet-derived growth factor mRNA. J Appl Physiol. 1992;73:2255–2262. PMID: 1490932. doi:10.1152/jappl.1992.73.6.2255
  • Wedgwood S, Dettman RW, Black SM. ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species. Am J Physiol Lung Cell Mol Physiol. 2001;281:L1058–1067. PMID: 11597896. doi:10.1152/ajplung.2001.281.5.L1058
  • Cheng TH, Shih NL, Chen SY, et al. Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells. J Mol Cell Cardiol. 2001;33:1805–1814. PMID: 11603923. doi:10.1006/jmcc.2001.1444
  • Tate RM, Morris HG, Schroeder WR, Repine JE. Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs. J Clin Investig. 1984;74:608–613. PMID: 6547730. doi:10.1172/JCI111458
  • Lee DS, McCallum EA, Olson DM. Effects of reactive oxygen species on prostacyclin production in perinatal rat lung cells. J Appl Physiol. 1989;66:1321–1327. PMID: 2651389. doi:10.1152/jappl.1989.66.3.1321
  • Brito R, Castillo G, González J, et al. Oxidative stress in hypertension: mechanisms and therapeutic opportunities. Exp Clin Endocrinol Diabetes. 2015;123:325–335. PMID: 25918881. doi:10.1055/s-0035-1548765
  • Block K, Gorin Y, Hoover P, et al. NAD(P)H oxidases regulate HIF-2alpha protein expression. J Biol Chem. 2007;282:8019–8026. PMID: 17200123. doi:10.1074/jbc.M611569200
  • Chandel NS, McClintock DS, Feliciano CE, et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia A mechanism of O2 sensing. J Biol Chem. 2000;275:25130–25138. PMID: 10833514. doi:10.1074/jbc.M001914200
  • Gale DP, Harten SK, Reid CDL, et al. Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2α mutation. Blood. 2008;112:919–921. PMID: 18650473. doi:10.1182/blood-2008-04-153718
  • Brusselmans K, Compernolle V, Tjwa M, et al. Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Investig. 2003;111:1519–1527. PMID: 12750401. doi:10.1172/JCI15496
  • Cracowski JL, Cracowski C, Bessard G, et al. Increased lipid peroxidation in patients with pulmonary hypertension. Am J Respir Crit Care Med. 2001;164:1038–1042. PMID: 11587993. doi:10.1164/ajrccm.164.6.2104033
  • Wong C-M, Bansal G, Pavlickova L, et al. Reactive oxygen species and antioxidants in pulmonary hypertension. Antioxid Redox Signal. 2013;18:1789–1796. PMID: 22657091. doi:10.1089/ars.2012.4568
  • Tabima DM, Frizzell S, Gladwin MT. Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radic Biol Med. 2012;52:1970–1986. PMID: 22401856. doi:10.1016/j.freeradbiomed.2012.02.041
  • Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens. 2010;28:201–212. PMID: 20051913. doi:10.1097/HJH.0b013e328332bcdb
  • Xu D, Guo H, Xu X, et al. Exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase. Hypertens. 2011;58:303–309. PMID: 21730301. doi:10.1161/HYPERTENSIONAHA.110.166819
  • Yu H, Liu J, Dong Y, et al. Anti-hypoxic effect of dihydroartemisinin on pulmonary artery endothelial cells. Biochem Biophys Res Commun. 2018;506:840–846. PMID: 30391003. doi:10.1016/j.bbrc.2018.10.176
  • Galhotra P, Prabhakar P, Meghwani H, et al. Beneficial effects of fenofibrate in pulmonary hypertension in rats. Mol Cell Biochem. 2018;449:185–194. PMID: 29761247. doi:10.1007/s11010-018-3355-3
  • Türck P, Lacerda DS, Carraro CC, et al. Trapidil improves hemodynamic, echocardiographic and redox state parameters of right ventricle in monocrotaline-induced pulmonary arterial hypertension model. Biomed Pharmacother. 2018;103:182–190. PMID: 29653363. doi:10.1016/j.biopha.2018.04.001
  • Zuckerbraun BS, Shiva S, Ifedigbo E, et al. Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation. 2010;121:98–109. PMID: 20026772. doi:10.1161/CIRCULATIONAHA.109.891077
  • Baliga RS, Milsom AB, Ghosh SM, et al. Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation. 2012;125:2922–2932. PMID: 22572914. doi:10.1161/CIRCULATIONAHA.112.100586
  • Sharp J, Farha S, Park MM, et al. Coenzyme Q supplementation in pulmonary arterial hypertension. Redox Biol. 2014;2:884–891. PMID: 25180165. doi:10.1016/j.redox.2014.06.010
  • Archer SL, Nelson DP, Weir EK. Detection of activated O2 species in vitro and in rat lungs by chemiluminescence. J Appl Physiol. 1989;67:1912–1921. PMID: 2532194. doi:10.1152/jappl.1989.67.5.1912
  • Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006;58:87–114. PMID: 16507884. doi:10.1124/pr.58.1.6
  • Poss WB, Huecksteadt TP, Panus PC, et al. Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia. Am J Physiol Lung Cell Mol Physiol. 1996;270:L941–L946. PMID: 8764218. doi:10.1152/ajplung.1996.270.6.L941
  • Engerson TD, McKelvey TG, Rhyne DB, et al. Conversion of xanthine dehydrogenase to oxidase in ischemic rat tissues. J Clin Invest. 1987;79:1564–1570. PMID: 3294898. doi:10.1172/JCI112990
  • Pritsos CA. Cellular distribution, metabolism and regulation of the xanthine oxidoreductase enzyme system. Chem Biol Interact. 2000;129:195–208. PMID: 11154741. doi:10.1016/s0009-2797(00)00203-9
  • Houston M, Estevez A, Chumley P, et al. Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem. 1999;274:4985–4994. PMID: 9988743. doi:10.1074/jbc.274.8.4985
  • Hoshikawa Y, Ono S, Suzuki S, et al. Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol. 2001;90:1299–1306. PMID: 11247927. doi:10.1152/jappl.2001.90.4.1299
  • Jankov RP, Kantores C, Pan J, Belik J. Contribution of xanthine oxidase‐derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol. 2008;294:L233–L245. PMID: 18083771. doi:10.1152/ajplung.00166.2007
  • Voelkel MA, Wynne KM, Badesch DB, et al. Hyperuricemia in severe pulmonary hypertension. Chest. 2000;117:19–24. PMID: 10631193. doi:10.1378/chest.117.1.19
  • Bendayan D, Shitrit D, Ygla M, et al. Hyperuricemia as a prognostic factor in pulmonary arterial hypertension. Respir Med. 2003;97:130–133. PMID: 12587962. doi:10.1053/rmed.2003.1440
  • Spiekermann S, Schenk K, Hoeper MM. Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension. Eur Respir J. 2009;34(1):276. PMID: 19567609. doi:10.1183/09031936.00013309
  • Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn‐SOD (SOD1), Mn‐SOD (SOD2), and EC‐SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002;33:337–349. PMID: 12126755. doi:10.1016/s0891-5849(02)00905-x
  • Eble JA, Niland S. The extracellular matrix of blood vessels. Curr Pharm Des. 2009;15:1385–1400. PMID: 19355976. doi:10.2174/138161209787846757
  • Lammers SR, Kao PH, Qi HJ, et al. Changes in the structure-function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves. Am J Physiol Heart Circ Physiol. 2008;295:H1451–9. PMID: 18660454. doi:10.1152/ajpheart.00127.2008
  • Frisdal E, Gest V, Vieillard-Baron A, et al. Gelatinase expression in pulmonary arteries during experimental pulmonary hypertension. Eur Respir J. 2001;18:838–845. PMID: 11757635. doi:10.1183/09031936.01.00084601
  • Ambalavanan N, Nicola T, Li P, et al. Role of matrix metalloproteinase-2 in newborn mouse lungs under hypoxic conditions. Pediatr Res. 2008;63:26–32. PMID: 18043506. doi:10.1203/PDR.0b013e31815b690d
  • Novotná J, Herget J. Possible role of matrix metalloproteinases in reconstruction of peripheral pulmonary arteries induced by hypoxia. Physiol Res. 2002;51:323–334. PMID: 12449429.
  • Lepetit H, Eddahibi S, Fadel E, et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J. 2005;25:834–842. PMID: 15863640. doi:10.1183/09031936.05.00072504
  • Thenappan T, Chan SY, Weir EK. Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol. 2018;315(5):H1322–H1331. PMID: 30141981. doi:10.1152/ajpheart.00136.2018
  • George J, D’Armiento J. Transgenic expression of human matrix metalloproteinase-9 augments monocrotaline-induced pulmonary arterial hypertension in mice. J Hypertens. 2011;29(2):299–308. PMID: 21063214. doi:10.1097/HJH.0b013e328340a0e4
  • Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest. 2000;105(1):21–34. PMID: 10619858. doi:10.1172/JCI6539
  • Cowan KN, Heilbut A, Humpl T, et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med. 2000;6(6):698–702. PMID: 10835689. doi:10.1038/76282
  • Vieillard-Baron A, Frisdal E, Raffestin B, et al. Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats. Hum Gene Ther. 2003;14(9):861–869. PMID: 12828857. doi:10.1089/104303403765701150
  • Pullamsetti S, Krick S, Yilmaz H, et al. Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration. Respir Res. 2005;6(128):1–14. PMID: 16262900. doi:10.1186/1465-9921-6-128
  • Martinez MLL, Lopes LF, Coelho EB, et al. Lercanidipine reduces matrix metalloproteinase-9 activity in patients with hypertension. J Cardiovasc Pharmacol. 2006;47(1):117–122. PMID: 16262900. doi:10.1097/01.fjc.0000196241.96759.71
  • Tayebjee MH, Nadar S, Blann AD, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Am J Hypertens. 2004;17(9):764–769. PMID: 15363817. doi:10.1016/j.amjhyper.2004.05.019
  • Mawatari E, Hongo M, Sakai A, et al. Amlodipine prevents monocrotaline-induced pulmonary arterial hypertension and prolongs survival in rats independent of blood pressure lowering. Clin Exp Pharmacol Physiol. 2007;34(7):594–600. PMID: 17581214. doi:10.1111/j.1440-1681.2007.04618.x.
  • Koo HS, Kim KC, Hong YM. Gene expressions of nitric oxide synthase and matrix metalloproteinase-2 in monocrotaline induced pulmonary hypertension in rats after bosentan treatment. Korean Circ J. 2011;41(2):83–90. PMID: 21430993. doi:10.4070/kcj.2011.41.2.83
  • Zaidi SHE, You X-M, Ciura S, et al. Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation. 2002;105(4):516–521. PMID: 11815437. doi:10.1161/hc0402.102866
  • Nickel NP, Spiekerkoetter E, Gu M, et al. Elafin reverses pulmonary hypertension via caveolin-1-dependent bone morphogenetic protein signaling. Am J Respir Crit Care Med. 2015;191:1273–1286. PMID: 25853696. doi:10.1164/rccm.201412-2291OC
  • Sutliff RL, Kang BY, Hart CM. PPARgamma as a potential therapeutic target in pulmonary hypertension. Ther Adv Respir Dis. 2010;4:143–160. PMID: 20530063. doi:10.1177/1753465809369619
  • Ameshima S, Golpon H, Cool CD, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res. 2003;92:1162–1169. PMID: 12714563. doi:10.1161/01.RES.0000073585.50092.14
  • Hansmann G, Zamanian RT. PPARgamma activation: a potential treatment for pulmonary hypertension. Sci Transl Med. 2009;1:12–14. PMID: 20371457. doi:10.1126/scitranslmed.3000267
  • Tian J, Smith A, Nechtman J, et al. Effect of PPARgamma inhibition on pulmonary endothelial cell gene expression: gene profiling in pulmonary hypertension. Physiol Genomics. 2009;40:48–60. PMID: 19825830. doi:10.1152/physiolgenomics.00094.2009
  • Lu X, Murphy TC, Nanes MS, Hart CM. PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol. 2010;299:L559–566. PMID: 20622120. doi:10.1152/ajplung.00090.2010
  • Calvier L, Chouvarine P, Legchenko E, Hansmann G. Transforming growth factor β1- and bone morphogenetic protein 2/PPARγ-regulated miRNAs in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2017;196:1227–1228. PMID: 28653861. doi:10.1164/rccm.201705-0923LE
  • Calvier L, Chouvarine P, Legchenko E, et al. PPARγ links BMP2 and TGFβ1 pathways in vascular smooth muscle cells, regulating cell proliferation and glucose metabolism. Cell Metab. 2017;25:1118–1134.e7. PMID: 28467929. doi:10.1016/j.cmet.2017.03.011
  • Geraci MW, Moore M, Gesell T, et al. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res. 2001;88:555–562. PMID: 11282888. doi:10.1161/01.res.88.6.555
  • Green DE, Murphy TC, Kang BY, et al. PPARgamma ligands attenuate hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of MicroRNA-21. PLoS One. 2015;10(7):e0133391. PMID: 26208095. doi:10.1371/journal.pone.0133391
  • Matsuda Y, Hoshikawa Y, Ameshima S, et al. Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats. Nihon Kokyuki Gakkai Zasshi. 2005;43:283–288. PMID: 15969209.
  • Nisbet RE, Bland JM, Kleinhenz DJ, et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol. 2010;42:482–490. PMID: 19520921. doi:10.1165/rcmb.2008-0132OC
  • Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator‐activated receptor‐gamma activation. Circulation. 2007;115:1275–1284. PMID: 17339547. doi:10.1161/CIRCULATIONAHA.106.663120
  • Kim EK, Lee JH, Oh YM, et al. Rosiglitazone attenuates hypoxia‐induced pulmonary arterial hypertension in rats. Respirology. 2010;15:659–668. PMID: 20546541. doi:10.1111/j.1440-1843.2010.01756.x.
  • Behringer A, Trappiel M, Berghausen EM, et al. Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension. Arch Pharmacol. 2016;389(4):369–379. PMID: 26742933. doi:10.1007/s00210-015-1205-3
  • Legchenko E, Chouvarine P, Borchert P, et al. Pparγ agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. Sci Transl Med. 2018;10(438):eaao0303. PMID: 29695452. doi:10.1126/scitranslmed.aao0303
  • Mannucci E, Monami M, Di Bari M, et al. Cardiac safety profile of rosiglitazone: a comprehensive meta‐analysis of randomized clinical trials. Int J Cardiol. 2010;143:135–140. PMID: 19328563. doi:10.1016/j.ijcard.2009.01.064
  • Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6. PMID: 23415113. doi:10.1186/1758-5996-5-6
  • Wu Y, Liu L, Zhang Y, et al. Activation of AMPK inhibits pulmonary arterial smooth muscle cells proliferation. Exp Lung Res. 2014;40:251–258. PMID: 24809794. doi:10.3109/01902148.2014.913092.
  • Davis BJ, Xie Z, Viollet B, Zou MH. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006;55:496–505. PMID: 16443786. doi:10.2337/diabetes.55.02.06.db05-1064
  • Zou MH, Kirkpatrick SS, Davis BJ, et al. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem. 2004;279:43940–43951. PMID: 15265871. doi:10.1074/jbc.M404421200
  • Dean A, Nilsen M, Loughlin L, et al. Metformin reverses development of pulmonary hypertension via aromatase inhibition. Hypertension. 2016;68(2):446–454. PMID: 27296990. doi:10.1161/HYPERTENSIONAHA.116.07353
  • Agard C, Rolli‐Derkinderen M, Dumas‐de‐La‐Roque E, et al. Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension. Br J Pharmacol. 2009;158:1285–1294. PMID: 19814724. doi:10.1111/j.1476-5381.2009.00445.x
  • Maron BA, Leopold JA. Emerging concepts in the molecular basis of pulmonary arterial hypertension: part II: neurohormonal signaling contributes to the pulmonary vascular and right ventricular pathophenotype of pulmonary arterial hypertension. Circulation. 2015;131:2079–2091. PMID: 26056345. doi:10.1161/CIRCULATIONAHA.114.006980
  • Vaillancourt M, Chia P, Sarji S, et al. Autonomic nervous system involvement in pulmonary arterial hypertension. Respir Res. 2017;18(1):201. PMID: 29202826. doi:10.1186/s12931-017-0679-6
  • Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation. 2000;102:865–870. PMID: 10952954. doi:10.1161/01.cir.102.8.865
  • Nootens M, Kaufmann E, Rector T, et al. Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic variables and endothelin levels. J Am Coll Cardiol. 1995;26:1581–1585. PMID: 7594089. doi:10.1016/0735-1097(95)00399-1
  • Bristow MR, Minobe W, Rasmussen R, et al. Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J Clin Investig. 1992;89:803–815. PMID: 1311717. doi:10.1172/JCI115659
  • Piao L, Fang YH, Parikh KS, et al. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation. 2012;126:2859–2869. PMID: 23124027. doi:10.1161/CIRCULATIONAHA.112.109868
  • Ishikawa M, Sato N, Asai K, et al. Effects of a pure alpha/beta‐adrenergic receptor blocker on monocrotaline‐induced pulmonary arterial hypertension with right ventricular hypertrophy in rats. Circ J. 2009;73:2337–2341. PMID: 19822980. doi:10.1253/circj.cj-09-0213
  • Ghosh S, Gupta M, Xu W, et al. Phosphorylation inactivation of endothelial nitric oxide synthesis in pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol. 2016;310:L1199–L1205. PMID: 27130529. doi:10.1152/ajplung.00092.2016
  • Perros F, Ranchoux B, Izikki M, et al. Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension. J Am Coll Cardiol. 2015;65:668–680. PMID: 25677428. doi:10.1016/j.jacc.2014.11.050
  • Perros F, De man FS, Bogaard HJ, et al. Use of β‐blockers in pulmonary hypertension. Circ Heart Fail. 2017;10(4):e003703. PMID: 28364092. doi:10.1161/CIRCHEARTFAILURE.116.003703
  • Bogaard HJ, Natarajan R, Mizuno S, et al. Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats. Am J Respir Crit Care Med. 2010;182:652–660. PMID: 20508210. doi:10.1164/rccm.201003-0335OC
  • Drake JI, Gomez-Arroyo J, Dumur CI, et al. Chronic carvedilol treatment partially reverses the right ventricular failure transcriptional profile in experimental pulmonary hypertension. Physiol Genom. 2013;45:449–461. PMID: 23632417. doi:10.1152/physiolgenomics.00166.2012
  • de Man FS, Handoko ML, van Ballegoij JJ, et al. Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension. Circ Heart Fail. 2012;5:97–105. PMID: 22157723. doi:10.1161/CIRCHEARTFAILURE.111.964494
  • Grinnan D, Bogaard HJ, Grizzard J, et al. Treatment of group I pulmonary arterial hypertension with carvedilol is safe. Am J Respir Crit Care Med. 2014;189:1562–1564. PMID: 24930531. doi:10.1164/rccm.201311-2025LE
  • Farha S, Saygin D, Park MM, et al. Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trial. JCI Insight. 2017;2(16):e95240. PMID: 28814664. doi:10.1172/jci.insight.95240
  • van Campen JS, de Boer K, van de Veerdonk MC, et al. Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study. Eur Respir J. 2016;48:787–796. PMID: 27390285. doi:10.1183/13993003.00090-2016
  • de Man FS, Tu L, Handoko ML, et al. Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:780–789. PMID: 22859525. doi:10.1164/rccm.201203-0411OC
  • Morrell NW, Danilov SM, Satyan KB, et al. Right ventricular angiotensin converting enzyme activity and expression is increased during hypoxic pulmonary hypertension. Cardiovasc Res. 1997;34:393–403. PMID: 9205554. doi:10.1016/s0008-6363(97)00049-7
  • Morrell NW, Atochina EN, Morris KG, et al. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. J Clin Invest. 1995;96:1823–1833. PMID: 7560074. doi:10.1172/JCI118228
  • Morrell NW, Morris KG, Stenmark KR. Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension. Am J Physiol. 1995;269:H1186–94. PMID: 7485548. doi:10.1152/ajpheart.1995.269.4.H1186
  • Alpert MA, Pressly TA, Mukerji V, et al. Short- and long-term hemodynamic effects of captopril in patients with pulmonary hypertension and selected connective tissue disease. Chest. 1992;102:1407–1412. PMID: 1424860. doi:10.1378/chest.102.5.1407
  • Ikram H, Maslowski AH, Nicholls MG, et al. Haemodynamic and hormonal effects of captopril in primary pulmonary hypertension. Br Heart J. 1982;48:541–545. PMID: 6756445. doi:10.1136/hrt.48.6.541
  • Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. Biochem Pharmacol. 2008;75:781–786. PMID: 17897633. doi:10.1016/j.bcp.2007.08.012
  • Tallant EA, Lu X, Weiss RB, et al. Bovine aortic endothelial cells contain an angiotensin-(1–7) receptor. Hypertension. 1997;29:388–393. PMID: 9039132. doi:10.1161/01.hyp.29.1.388
  • Ferrario CM, Chappell MC, Tallant EA, et al. Counterregulatory actions of angiotensin-(1–7). Hypertension. 1997;30:535–541. PMID: 9322978. doi:10.1161/01.hyp.30.3.535
  • Brosnihan KB, Li P, Ferrario CM. Angiotensin-(1–7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996;27:523–528. PMID: 8613197. doi:10.1161/01.hyp.27.3.523
  • Nakamoto H, Ferrario CM, Fuller SB, et al. Angiotensin-(1–7) and nitric oxide interaction in renovascular hypertension. Hypertension. 1995;25:796–802. PMID: 7536715. doi:10.1161/01.hyp.25.4.796
  • Tan WSD, Liao W, Zhou S, et al. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases. Curr Opin Pharmacol. 2018;40:9–17. PMID: 29288933. doi:10.1016/j.coph.2017.12.002
  • Hemnes AR, Rathinasabapathy A, Austin EA, et al. A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension. Eur Respir J. 2018;51(6):pii: 1702638. PMID: 29903860. doi:10.1183/13993003.02638-2017
  • Maron BA, Leopold JA. Aldosterone receptor antagonists: effective but often forgotten. Circulation. 2010;121:934–939. PMID: 20177008. doi:10.1161/CIRCULATIONAHA.109.895235
  • Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized aldactone evaluation study investigators. N Engl J Med. 1999;341:709–717. PMID: 10471456. doi:10.1056/NEJM199909023411001
  • Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. 2006;55(suppl6):vi1–vi12. PMID: 16966752. doi:10.1136/gut.2006.099580
  • Maron BA, Opotowsky AR, Landzberg MJ, et al. Plasma aldosterone levels are elevated in patients with pulmonary arterial hypertension in the absence of left ventricular heart failure: a pilot study. Eur J Heart Fail. 2013;15:277–283. PMID: 23111998. doi:10.1093/eurjhf/hfs173
  • Maron BA, Zhang YY, White K, et al. Aldosterone inactivates the endothelin‐B receptor via a cysteinyl thiol redox switch to decrease pulmonary endothelial nitric oxide levels and modulate pulmonary arterial hypertension. Circulation. 2012;126:963–974. PMID: 22787113. doi:10.1161/CIRCULATIONAHA.112.094722
  • Maron BA, Oldham WM, Chan SY, et al. Upregulation of steroidogenic acute regulatory protein by hypoxia stimulates aldosterone synthesis in pulmonary artery endothelial cells to promote pulmonary vascular fibrosis. Circulation. 2014;130:168–179. PMID: 25001622. doi:10.1161/CIRCULATIONAHA.113.007690
  • Aghamohammadzadeh R, Zhang YY, Stephens TE, et al. Up‐regulation of the mammalian target of rapamycin complex 1 subunit raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension. FASEB J. 2016;30(7):2511–2527. PMID: 27006450. doi:10.1096/fj.201500042
  • Safdar Z, Frost A, Basant A, et al. Spironolactone in pulmonary arterial hypertension: results of a cross-over study. Pulm Circ. 2020;10(2):2045894019898030. PMCID: PMC7219009. PMID: 32426108. doi:10.1177/2045894019898030
  • Maron BA, Waxman AB, Opotowsky AR, et al. Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] Study 1 and 2 Trials). Am J Cardiol. 2013;112(5):720–725. PMID: 23751938. doi:10.1016/j.amjcard.2013.04.051
  • Hobbs AJ. Soluble guanylate cyclase: the forgotten sibling. Trends Pharmacol Sci. 1997;18(12):484–491. PMID: 9458697. doi:10.1016/s0165-6147(97)01137-1
  • Casserly B, Klinger JR. Brain natriuretic peptide in pulmonary arterial hypertension: biomarker and potential therapeutic agent. Drug Des Devel Ther. 2009;3:269–287. PMID: 20054445. doi:10.2147/dddt.s4805
  • Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006;27(1):47–72. PMID: 16291870. doi:10.1210/er.2005-0014
  • Rosenkranz AC, Woods RL, Dusting GJ, Ritchie RH. Antihypertrophic actions of the natriuretic peptides in adult rat cardiomyocytes: importance of cyclic GMP. Cardiovasc Res. 2003;57(2):515–522. PMID: 12566124. doi:10.1016/s0008-6363(02)00667-3
  • Klinger JR, Petit RD, Curtin LA, et al. Cardiopulmonary responses to chronic hypoxia in transgenic mice that overexpress ANP. J Appl Physiol. 1993;75(1):198–205. PMID: 7690745. doi:10.1152/jappl.1993.75.1.198.
  • Hill NS, Klinger JR, Warburton RR, Pietras L, Wrenn DS. Brain natriuretic peptide: possible role in the modulation of hypoxic pulmonary hypertension. Am J Physiol. 1994;266(3 Pt 1):L308–15. PMID: 8166300. doi:10.1152/ajplung.1994.266.3.L308
  • Angus RM, McCallum MJ, Hulks G, et al. Bronchodilator, cardiovascular, and cyclic guanylyl monophosphate response to high-dose infused atrial natriuretic peptide in asthma. Am Rev Respir Dis. 1993;147(5):1122–1125. PMID: 8387254. doi:10.1164/ajrccm/147.5.1122
  • Baliga RS, Zhao L, Madhani M, et al. Synergy between natriuretic peptides and phosphodiesterase 5 inhibitors ameliorates pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178(8):861–869. PMID: 18689467. doi:10.1164/rccm.200801-121OC
  • Klinger JR, Houtchens J, Thaker S, et al. Acute cardiopulmonary hemodynamic effects of brain natriuretic peptide in patients with pulmonary arterial hypertension. Chest. 2005;128(6Suppl):618S–619S. PMID: 16373873. doi:10.1378/chest.128.6_suppl.618S-a
  • Klinger JR, Thaker S, Houtchens J, et al. Pulmonary hemodynamic responses to brain natriuretic peptide and sildenafil in patients with pulmonary arterial hypertension. Chest. 2006;129(2):417–425. PMID: 16478861. doi:10.1378/chest.129.2.417
  • Klinger JR, Warburton RR, Pietras L, Hill NS. Brain natriuretic peptide inhibits hypoxic pulmonary hypertension in rats. J Appl Physiol. 1998;84(5):1646–1652. PMID: 9572812. doi:10.1152/jappl.1998.84.5.1646
  • Jin H, Yang RH, Chen YF, Jackson RM, Oparil S. Atrial natriuretic peptide attenuates the development of pulmonary hypertension in rats adapted to chronic hypoxia. J Clin Invest. 1990;85(1):115–120. PMID: 2136863. doi:10.1172/JCI114400.
  • Kapoun AM, Liang F, O’Young G, et al. B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. Circ Res. 2004;94(4):453–461. PMID: 14726474. doi:10.1161/01.RES.0000117070.86556.9F
  • VMAC Investigators. (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs. nitroglycerin for treatment of congestive heart failure. A randomized controlled trial. JAMA. 2002;287(12):1531–1540. PMID: 11911755. doi:10.1001/jama.287.12.1531
  • Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heartfailure. N Engl J Med. 2000;343(4):246–253. PMID: 10911006. doi:10.1056/NEJM200007273430403
  • Mills RM, LeJemtel TH, Horton DP, et al. Sustained hemodynamic effects of an infusion of nesiritide (human B-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. Natrecor Study Group. J Am Coll Cardiol. 1999;34:155–162. PMID: 10400005. doi:10.1016/s0735-1097(99)00184-9
  • Michaels AD, Chatterjee K, De Marco T. Effects of intravenous nesiritide on pulmonary vascular hemodynamics in pulmonary hypertension. J Card Fail. 2005;11(6):425–431. PMID: 16105633. doi:10.1016/j.cardfail.2005.01.009
  • Gunaydin S, Imai Y, Takanashi T, et al. The effects of vasoactive intestinal peptide on monocrotaline induced pulmonary hypertensive rabbits following cardiopulmonary bypass: a comparative study with isoproterenol and nitroglycerine. Cardiovasc Surg. 2002;10(2):138–145. PMID: 11888743. doi:10.1016/s0967-2109(01)00126-0
  • Söderman C, Eriksson LS, Juhlin-Dannfelt A, Lundberg JM, Broman L, Holmgren A. Effect of vasoactive intestinal polypeptide (VIP) on pulmonary ventilation-perfusion relationships and central haemodynamics in healthy subjects. Clin Physiol. 1993;13(6):677–685. PMID: 8119061. doi:10.1111/j.1475-097x.1993.tb00482.x
  • Maruno K, Absood A, Said SI. VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells. Am J Physiol. 1995;268(6 Pt 1):L1047–51. PMID: 7541947. doi:10.1152/ajplung.1995.268.6.L1047
  • Cox CP, Linden J, Said SI. VIP elevates platelet cyclic AMP (cAMP) levels and inhibits in vitro platelet activation induced by platelet-activating factor (PAF). Peptides. 1984;5(2):325–328. PMID: 6206481. doi:10.1016/0196-9781(84)90228-6
  • Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111(9):1339–1346. PMID: 12727925 PMID: 12727925. doi:10.1172/JCI17500
  • Galie N, Boonstra A, Ewert R. Effects of inhaled aviptadil (Vasoactive Intestinal Peptide) in patients with pulmonary arterial hypertension (PAH). Am J Resp Crit Care Med. 2010;181:A2516.
  • Nicholls MG, Lainchbury JG, Lewis LK, et al. Bioactivity of adrenomedullin and proadrenomedullin N-terminal 20 peptide in man. Peptides. 2001;22(11):1745–1752. PMID: 11754960. doi:10.1016/s0196-9781(01)00508-3
  • Kakishita M, Nishikimi T, Okano Y, et al. Increased plasma levels of adrenomedullin in patients with pulmonary hypertension. Clin Sci (Lond). 1999;96(1):33–39. PMID: 9857104. doi:10.1042/CS19980070
  • Shimukubo T, Sakata J, Kitamura K, Kangawa K, Matsuo H, Eto T. Augmented adrenomedullin concentrations in right ventricle and plasma of experimental pulmonary hypertension. Life Sci. 1995;57(19):1771–1779. PMID: 7475919. doi:10.1016/0024-3205(95)02155-c
  • Yoshibayashi M, Kamiya T, Kitamura K, et al. Plasma levels of adrenomedullin in primary and secondary pulmonary hypertension in patients <20 years of age. Am J Cardiol. 1997;79(11):1556–1558. PMID: 9185657. doi:10.1016/s0002-9149(97)00195-1
  • Nishikimi T, Nagata S, Sasaki T, et al. Plasma concentrations of adrenomedullin correlate with the extent of pulmonary hypertension in patients with mitral stenosis. Heart. 1997;78(4):390–395. PMID: 9404257. doi:10.1136/hrt.78.4.390
  • Yoshihara F, Nishikimi T, Horio T, et al. Eur Chronic infusion of adrenomedullin reduces pulmonary hypertension and lessens right ventricular hypertrophy in rats administered monocrotaline. J Pharmacol. 1998;355(1):33–39. PMID: 9754936. doi:10.1016/s0014-2999(98)00475-0
  • Nagaya N, Nishikimi T, Uematsu M, et al. Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension. Heart. 2000;84(6):653–658. PMID: 11083748. doi:10.1136/heart.84.6.653
  • Nagaya N, Miyatake K, Kyotani S, et al. Pulmonary vasodilator response to adrenomedullin in patients with pulmonary hypertension. Hypertens Res. 2003;26(Suppl):S141–6. PMID: 12630825. doi:10.1291/hypres.26.s141
  • Nagaya N, Kyotani S, Uematsu M, et al. Effects of adrenomedullin inhalation on hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Circulation. 2004;109(3):351–356. PMID: 14718403. doi:10.1161/01.CIR.0000109493.05849.14
  • Giordano N, Papakostas P, Lucani B, et al. Serum relaxin in systemic sclerosis. J Rheumatol. 2005;32:2164–2166. PMID: 16265695.
  • Tozzi CA, Poiani GJ, McHugh NA, et al. Recombinant human relaxin reduces hypoxic pulmonary hypertension in the rat. Pulm Pharmacol Ther. 2005;18:346–353. PMID: 15939313. doi:10.1016/j.pupt.2005.01.003
  • Mazurek JA, Horne BD, Kelesidis I, et al. Relaxin levels in pulmonary hypertension: a comparison between pulmonary arterial hypertension and diastolic heart failure-induced pulmonary hypertension. J Heart Lung Transplant. 2013;32(3):371–374. PMID: 23273743. doi:10.1016/j.healun.2012.11.030
  • Lee SL, Simon AR, Wang WW, Fanburg BL. H(2)O(2) signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2001;281(3):L646–52. doi:10.1152/ajplung.2001.281.3.L646
  • Eddahibi S, Guignabert C, Barlier-Mur AM, et al. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation. 2006;113(15):1857–1864. PMID: 16606791. doi:10.1161/CIRCULATIONAHA.105.591321
  • Morrell NW, Archer SL, Stenmark KR, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12Suppl S):13S–24S. PMID: 15194174. doi:10.1016/j.jacc.2004.02.029
  • MacLean MR, Herve P, Eddahibi S, Adnot S. 5-hydroxytryptamine and the pulmonary circulation: receptors, transporters and relevance to pulmonary arterial hypertension. Br J Pharmacol. 2000;131(2):161–168. doi:10.1038/sj.bjp.0703570
  • Morecroft I, Heeley RP, Prentice HM, Kirk A, MacLean MR. 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor. Br J Pharmacol. 1999;128(3):730–734. PMID: 10516655. doi:10.1038/sj.bjp.0702841
  • Wilson SM, Mason HS, Ng LC, et al. Role of basal extracellular Ca2+ entry during 5-HT-induced vasoconstriction of canine pulmonary arteries. Br J Pharmacol. 2005;144(2):252–264. PMID: 15655514. doi:10.1038/sj.bjp.0706077
  • Liu Y, Fanburg BL. Serotonin-induced growth of pulmonary artery smooth muscle requires activation of phosphatidylinositol 3-kinase/serine-threonine protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase 1. Am J Respir Cell Mol Biol. 2006;34(2):182–191. PMID: 16195541. doi:10.1165/rcmb.2005-0163OC
  • Mair KM, MacLean MR, Morecroft I, Dempsie Y, Palmer TM. Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. Br J Pharmacol. 2008;155(4):606–616. PMID: 18695640. doi:10.1038/bjp.2008.310
  • Hervé P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med. 1995;99(3):249–254. PMID: 7653484. doi:10.1016/s0002-9343(99)80156-9
  • Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;335(9):609–616. PMID: 8692238. doi:10.1056/NEJM199608293350901
  • Eddahibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest. 2001;108(8):1141–1150. PMID: 11602621. doi:10.1172/JCI12805
  • Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am J Physiol. 1997;272(5 Pt 1):L795–806. PMID: 9176241. doi:10.1152/ajplung.1997.272.5.L795
  • Kren V, Eich E, Pertz HH. Pergolide, terguride and N,N’-spacer-linked oligomers of both interact with 5-HT2A receptors of rat tail artery. Physiol Res. 2004;53(1):35–43. PMID: 14984312.
  • Millan MJ, Maiofiss L, Cussac D, et al. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther. 2002;303(2):791–804. PMID: 12388666. doi:10.1124/jpet.102.039867
  • Jähnichen S, Horowski R, Pertz HH. Agonism at 5-HT2B receptors is not a class effect of the ergolines. Eur J Pharmacol. 2005;513(3):225–228. PMID: 15862804. doi:10.1016/j.ejphar.2005.03.010
  • Dumitrascu R, Kulcke C, Königshoff M, et al. Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. Eur Respir J. 2011;37(5):1104–1118. PMID: 20947677. doi:10.1183/09031936.00126010
  • Ghofrani HA, Al-Hiti H, Vonk-Noordegraaf A, et al. Proof-of-concept study to investigate the efficacy, hemodynamics and tolerability of terguride vs. placebo in subjects with pulmonary arterial hypertension: results of A Double Blind, Randomised, Prospective Phase IIa Study. Am J Resp Crit Care Med. 2012;185:A2496.
  • Lahm T, Tuder RM, Petrache I. Progress in solving the sex hormone paradox in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2014;307(1):L7–26. PMID: 24816487. doi:10.1152/ajplung.00337.2013
  • Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med. 1987;107:216–223. PMID: 3605900. doi:10.7326/0003-4819-107-2-216
  • Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how reveal differs from historic and non‐us contemporary registries. Chest. 2011;139:128–137. PMID: 20558556. doi:10.1378/chest.10-0075
  • McGoon MD, Benza RL, Escribano‐Subias P, et al. Pulmonary arterial hypertension: epidemiology and registries. J Am Coll Cardiol. 2013;62:D51–D59. PMID: 24355642. doi:10.1016/j.jacc.2013.10.023
  • Prins KW, Thenappan T. World health organization group i pulmonary hypertension: epidemiology and pathophysiology. Cardiol Clin. 2016;34:363–374. PMID: 27443134. doi:10.1016/j.ccl.2016.04.001
  • Chen X, Austin ED, Talati M, et al. Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects. Eur Respir J. 2017;50:1602337. PMID: 28775043. doi:10.1183/13993003.02337-2016
  • Foderaro A, Ventetuolo CE. Pulmonary arterial hypertension and the sex hormone paradox. Curr Hypertens Rep. 2016;18(11):84. PMID: 27832457. doi:10.1007/s11906-016-0689-7
  • Ventetuolo CE, Baird GL, Barr RG, et al. Higher estradiol and lower dehydroepiandrosterone-sulfate levels are associated with pulmonary arterial hypertension in men. Am J Respir Crit Care Med. 2016;193:1168–1175. PMID: 26651504. doi:10.1164/rccm.201509-1785OC
  • Frump AL, Goss KN, Vayl A, et al. Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones. Am J Physiol Lung Cell Mol Physiol. 2015;308:L873–L890. PMID: 25713318. doi:10.1152/ajplung.00006.2015
  • Liu A, Philip J, Vinnakota KC, et al. Estrogen maintains mitochondrial content and function in the right ventricle of rats with pulmonary hypertension. Physiol Rep. 2017;5(6):e13157. PMID: 28320896. doi:10.14814/phy2.13157
  • Jacobs W, van de Veerdonk MC, Trip P, et al. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest. 2014;145(6):1230–1236. PMID: 24306900. doi:10.1378/chest.13-1291
  • Kawut SM, Al-Naamani N, Agerstrand C, et al. Determinants of right ventricular ejection fraction in pulmonary arterial hypertension. Chest. 2009;135(3):752–759. PMID: 18849396. doi:10.1378/chest.08-1758
  • Baird GL, Archer-Chicko C, Barr RG, et al. 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. 2018;51:1800467. PMID: 29954925. doi:10.1183/13993003.00467-2018
  • Simpson ER, Clyne C, Rubin G, et al. Aromatase—a brief overview. Annu Rev Physiol. 2002;64:93–127. PMID: 11826265. doi:10.1146/annurev.physiol.64.081601.142703
  • Burstein HJ, Griggs JJ, Prestrud AA, Temin S. American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor‐positive breast cancer. J Oncol Pract. 2010;6:243–246. PMID: 21197188. doi:10.1200/JOP.000082
  • Mair KM, Wright AF, Duggan N, et al. Sex‐dependent influence of endogenous estrogen in pulmonary hypertension. Am J Respir Crit Care Med. 2014;190:456–467. PMID: 24956156. doi:10.1164/rccm.201403-0483OC
  • Kawut SM, Archer‐Chicko CL, DeMichele A, et al. Anastrozole in pulmonary arterial hypertension. A randomized, double‐blind, placebo‐controlled trial. Am J Respir Crit Care Med. 2017;195:360–368. PMID: 27602993. doi:10.1164/rccm.201605-1024OC
  • Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. 2003;2:205–213. PMID: 12612646. doi:10.1038/nrd1031
  • van Empel VP, Lee J, Williams TJ, et al. Iron deficiency in patients with idiopathic pulmonary arterial hypertension. Heart Lung Circ. 2014;23:287–292. PMID: 24094431. doi:10.1016/j.hlc.2013.08.007
  • Rhodes CJ, Wharton J, Howard L, et al. Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target. Eur Respir J. 2011;38:1453–1460. PMID: 21478213. doi:10.1183/09031936.00037711
  • Ruiter G, Lankhorst S, Boonstra A, et al. Iron deficiency is common in idiopathic pulmonary arterial hypertension. Eur Respir J. 2011;37:1386–1391. PMID: 20884742. doi:10.1183/09031936.00100510
  • Soon E, Treacy CM, Toshner MR, et al. Unexplained iron deficiency in idiopathic and heritable pulmonary arterial hypertension. Thorax. 2011;66(4):326–332. PMID: 21297151. doi:10.1136/thx.2010.147272
  • Krasuski RA, Hart SA, Smith B, et al. Association of anemia and long-term survival in patients with pulmonary hypertension. Int J Cardiol. 2011;150(3):291–295. PMID: 20472313. doi:10.1016/j.ijcard.2010.04.038
  • Ruiter G, Manders E, Happe CM, et al. Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency. Pulm Circ. 2015;5(3):466–472. PMID: 26401247. doi:10.1086/682217
  • Viethen T, Gerhardt F, Dumitrescu D, et al. Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: a pilot study. Int J Cardiol. 2014;175:233–239. PMID: 24880481. doi:10.1016/j.ijcard.2014.04.233
  • Robinson JC, Graham BB, Rouault TC, et al. The crossroads of iron with hypoxia and cellular metabolism. Implications in the pathobiology of pulmonary hypertension. Am J Respir Cell Mol Biol. 2014;51(6):721–729. PMID: 24988529. doi:10.1165/rcmb.2014-0021TR
  • Callejo M, Mondejar-Parreño G, Esquivel-Ruiz S, et al. Total, bioavailable, and free vitamin D levels and their prognostic value in pulmonary arterial hypertension. J Clin Med. 2020;9(2):448. PMID: 32041235. doi:10.3390/jcm9020448
  • Yu H, Xu M, Dong Y, Liu J. (OH)2D3 attenuates pulmonary arterial hypertension via microRNA-204 mediated Tgfbr2/Smad signaling. Exp Cell Res. 2018;362(2):311–323. PMID: 29196166. doi:10.1016/j.yexcr.2017.11.032.
  • Mirdamadi A, Moshkdar P. Benefits from the correction of vitamin D deficiency in patients with pulmonary hypertension. Caspian J Intern Med. 2016;7(4):253–259. PMID: 27999642.
  • Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109:3122–3131. PMID: 15226229. doi:10.1161/01.CIR.0000133187.74800.B9
  • Pascal JM. The comings and goings of PARP-1 in response to DNA damage. DNA Repair (Amst). 2018;71:177–182. PMID: 30177435. doi:10.1016/j.dnarep.2018.08.022
  • Wheelhouse NM, Chan YS, Gillies SE, et al. TNF-alpha induced DNA damage in primary murine hepatocytes. Int J Mol Med. 2003;12:889–894. PMID: 14612962.
  • Fehsel K, Kolb-Bachofen V, Kolb H. Analysis of TNF alpha-induced DNA strand breaks at the single cell level. Am J Pathol. 1991;139:251–254. PMID: 1867316.
  • Gorenne I, Kumar S, Gray K, et al. Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation. 2013;127:386–396. PMID: 23224247. doi:10.1161/CIRCULATIONAHA.112.124404
  • Meloche J, Pflieger A, Vaillancourt M, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation. 2014;129:786–797. PMID: 24270264. doi:10.1161/CIRCULATIONAHA.113.006167
  • Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2014;117:421–426. PMID: 15137936. doi:10.1016/s0092-8674(04)00452-0
  • Sengupta A, Molkentin JD, Paik JH, et al. FoxO transcription factors promote cardiomyocyte survival upon induction of oxidative stress. J Biol Chem. 2011;286(9):7468–7478. doi:10.1074/jbc.M110.179242
  • Savai R, Al‐Tamari HM, Sedding D, et al. Pro‐proliferative and inflammatory signaling converge on FoXO1 transcription factor in pulmonary hypertension. Nat Med. 2014;20:1289–1300. PMID: 25344740. doi:10.1038/nm.3695
  • Deng C, Zhong Z, Wu D, et al. Role of FoxO1 and apoptosis in pulmonary vascular remolding in a rat model of chronic thromboembolic pulmonary hypertension. Sci Rep. 2017;7(1):2270. PMID: 28536427. doi:10.1038/s41598-017-02007-5
  • Nehate C, Jain S, Saneja A, et al. Paclitaxel formulations: challenges and novel delivery options. Curr Drug Deliv. 2014;11(6):666–686. PMID: 24909147. doi:10.2174/1567201811666140609154949
  • Veldhoen RA, Banman SL, Hemmerling DR, et al. The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene. 2013;32(6):736–746. PMID: 22430212. doi:10.1038/onc.2012.92
  • Goto T, Takano M, Hirata J, Tsuda H. The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers. Br J Cancer. 2008;98(6):1068–1075. PMID: 18319717. doi:10.1038/sj.bjc.6604279
  • Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell. 2013;152(6):1237–1251. PMID: 23498934. doi:10.1016/j.cell.2013.02.014
  • Yin Y, Wu X, Yang Z, et al. The potential efficacy of R8-modified paclitaxel loaded liposomes on pulmonary arterial hypertension. Pharm Res. 2013;30:2050–2062. PMID: 23756757. doi:10.1007/s11095-013-1058-8
  • Galié N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004;61(2):227–237. PMID: 14736539. doi:10.1016/j.cardiores.2003.11.026
  • Dai Y, Chen X, Song X, et al. Immunotherapy of endothelin-1 receptor Type A for pulmonary arterial hypertension. J Am Coll Cardiol. 2019;73(20):2567–2580. PMID: 31118151. doi:10.1016/j.jacc.2019.02.067
  • Fessel JP, Loyd JE, Austin ED. The genetics of pulmonary arterial hypertension in the postBMPR2 era. Pulm Circ. 2011;1(3):305–319. doi:10.4103/2045-8932.87293
  • Kaji EH, Leiden JM. Gene and stem cell therapies. JAMA. 2001;285(5):545–550. doi:10.1001/jama.285.5.545
  • Reynolds AM, Xia W, Holmes MD, et al. Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonaryhypertension. Am J Physiol Lung Cell Mol Physiol. 2007;292(5):L1182–92. doi:10.1152/ajplung.00020.2006
  • Lee CS, Bishop ES, Zhang R, et al. Adenovirus-mediated gene delivery: potential applications for gene and cell-based therapies in the new era of personalized medicine. Genes Dis. 2017;4(2):43–63. doi:10.1016/j.gendis.2017.04.001
  • Bisserier M, Pradhan N, Lahouaria H. Current and emerging therapeutic approaches to pulmonary hypertension. Rev Cardiovasc Med. 2020;21(2):163–179. doi:10.31083/j.rcm.2020.02.597
  • Lee R, Feinbaum R, Ambros V. A short history of a short RNA. Cell. 2004;116(Suppl):S89–S92,1 p. following S96. doi:10.1016/s0092-8674(04)00035-2
  • Filipowicz W, Bhattacharyya SN, Sonenberg N. Mechanisms of posttranscriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 2008;9(2):102–114. doi:10.1038/nrg2290
  • Giannakakis A, Sandaltzopoulos R, Greshock J, et al. miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer. Cancer Biol Ther. 2008;7(2):255–264. PMID: 18059191. doi:10.4161/cbt.7.2.5297
  • Fasanaro P, Greco S, Lorenzi M, et al. An integrated approach for experimental target identification of hypoxia-induced miR-210. J Biol Chem. 2009;284(50):35134–35143. PMID: 19826008. doi:10.1074/jbc.M109.052779
  • Li S, Ran Y, Zhang D, et al. MicroRNA-138 plays a role in hypoxic pulmonary vascular remodelling by targeting Mst1. Biochem J. 2013;452(2):281–291. PMID: 23485012. doi:10.1042/BJ20120680
  • Caruso P, Dempsie Y, Stevens HC, et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res. 2012;111(3):290–300. PMID: 22715469. doi:10.1161/CIRCRESAHA.112.267591
  • Gou D, Ramchandran R, Peng X, et al. miR-210 has an antiapoptotic effect in pulmonary artery smooth muscle cells during hypoxia. Am J Physiol Lung Cell Mol Physiol. 2012;303(8):L682–91. PMID: 22886504. doi:10.1152/ajplung.00344.2011
  • Kang K, Peng X, Zhang X, et al. MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells. J Biol Chem. 2013;288(35):25414–25427. PMID: 23853098. doi:10.1074/jbc.M113.460287
  • Courboulin A, Paulin R, Giguère NJ, et al. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208(3):535–548. PMID: 21321078. doi:10.1084/jem.20101812
  • Jalali S, Ramanathan GK, Parthasarathy PT, et al. Mir-206 regulates pulmonary artery smooth muscle cell proliferation and differentiation. PLoS One. 2012;7(10):e46808. doi:10.1371/journal.pone.0046808
  • Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009;27(5):351–357. PMID: 19711245. doi:10.1055/s-0029-1237423
  • Hambach L, Ling KW, Pool J, et al. Hypomethylating drugs convert HA-1 negative solid tumors into targets for stem cell based immunotherapy. Blood. 2009;113(12):2715–2722. PMID: 19096014. doi:10.1182/blood-2008-05-158956
  • Chueh AC, Tse JW, Tögel L, Mariadason JM. Mechanisms of histone deacetylase inhibitor-regulated gene expression in cancer cells. Antioxid Redox Signal. 2015;23(1):66–84. PMC 4492771. PMID 24512308. doi:10.1089/ars.2014.5863
  • Zhao L, Chen CN, Hajji N, et al. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation. 2012;126(4):455–467. PMID: 22711276. doi:10.1161/CIRCULATIONAHA.112.103176
  • Kim J, Kang Y, Kojima Y, et al. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013;19(1):74–82. PMID: 23263626. doi:10.1038/nm.3040
  • Kim J, Hwangbo C, Hu X, et al. Restoration of impaired endothelial myocyte enhancer factor 2 function rescues pulmonary arterial hypertension. Circulation. 2015;131(2):190–199. PMID: 25336633. doi:10.1161/CIRCULATIONAHA.114.013339
  • Borck PC, Guo LW, Plutzky J. BET epigenetic reader proteins in cardiovascular transcriptional programs. Circ Res. 2020;126(9):1190–1208. PMID: 32324495. doi:10.1161/CIRCRESAHA.120.315929
  • Meloche J, Potus F, Vaillancourt M, et al. Bromodomain-containing protein 4: the epigenetic origin of pulmonary arterial hypertension. Circ Res. 2015;117(6):525–535. PMID: 26224795. doi:10.1161/CIRCRESAHA.115.307004