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Current Vascular Pharmacology

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ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

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Review Article

Pharmacological Agents and Potential New Therapies in Pulmonary Arterial Hypertension

Author(s): Renata Trabach Santos, Maria Eduarda de Sá Freire Onofre, Dayene de Assis Fernandes Caldeira, Adriane Bello Klein, Patricia Rieken Macedo Rocco, Fernanda Ferreira Cruz and Pedro Leme Silva*

Volume 22, Issue 3, 2024

Published on: 19 December, 2023

Page: [155 - 170] Pages: 16

DOI: 10.2174/0115701611266576231211045731

Price: $65

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an imbalance between vasoactive mediators, which causes vascular remodeling, increased pulmonary vascular resistance, and right ventricular overload, ultimately leading to heart failure and death. A metabolic theory has been suggested to explain the pathophysiology of PAH whereby abnormalities in mitochondrial biogenesis can trigger a hyperproliferative and apoptosis-resistant phenotype in cardiopulmonary and malignant cells, leading to mitochondrial dysfunction, which in turn causes the Warburg effect. This can culminate in the mitophagy of pulmonary vessels and cardiomyocytes. The present narrative review focuses on the pathophysiology of PAH, the pharmacological agents currently available for its treatment, and promising and challenging areas of therapeutic investigation.

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[1]
Vazquez ZGS, Klinger JR. Guidelines for the treatment of pulmonary arterial hypertension. Lung 2020; 198(4): 581-96.
[http://dx.doi.org/10.1007/s00408-020-00375-w] [PMID: 32671468]
[2]
Galiè N, McLaughlin VV, Rubin LJ, Simonneau G. An overview of the 6th world symposium on pulmonary hypertension. Eur Respir J 2019; 53(1): 1802148.
[http://dx.doi.org/10.1183/13993003.02148-2018] [PMID: 30552088]
[3]
Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023; 61(1): 2200879.
[http://dx.doi.org/10.1183/13993003.00879-2022] [PMID: 36028254]
[4]
Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62(S25): D42-50.
[http://dx.doi.org/10.1016/j.jacc.2013.10.032] [PMID: 24355641]
[5]
Humbert M, Montani D, Evgenov OV, Simonneau G. Definition and classification of pulmonary hypertension. In: Humbert M, Evgenov OV, Stasch JP, Eds. Pharmacotherapy of Pulmonary Hypertension Berlin. Berlin, Heidelberg: Springer 2013; pp. 3-29.
[http://dx.doi.org/10.1007/978-3-642-38664-0_1]
[6]
Montani D, Günther S, Dorfmüller P, et al. Pulmonary arterial hypertension. Orphanet J Rare Dis 2013; 8(1): 97.
[http://dx.doi.org/10.1186/1750-1172-8-97] [PMID: 23829793]
[7]
Beshay S, Sahay S, Humbert M. Evaluation and management of pulmonary arterial hypertension. Respir Med 2020; 171: 106099.
[http://dx.doi.org/10.1016/j.rmed.2020.106099] [PMID: 32829182]
[8]
Poch D, Mandel J. Pulmonary hypertension. Ann Intern Med 2021; 174(4): ITC49-64.
[http://dx.doi.org/10.7326/AITC202104200] [PMID: 33844574]
[9]
Kim D, George MP. Pulmonary hypertension. Med Clin North Am 2019; 103(3): 413-23.
[http://dx.doi.org/10.1016/j.mcna.2018.12.002] [PMID: 30955510]
[10]
Maron BA, Abman SH, Elliott CG, et al. Pulmonary arterial hypertension: Diagnosis, treatment, and novel advances. Am J Respir Crit Care Med 2021; 203(12): 1472-87.
[http://dx.doi.org/10.1164/rccm.202012-4317SO] [PMID: 33861689]
[11]
Valverde AB, Soares JM, Viana KP, Gomes B, Soares C, Souza R. Pulmonary arterial hypertension in Latin America: Epidemiological data from local studies. BMC Pulm Med 2018; 18(1): 106.
[http://dx.doi.org/10.1186/s12890-018-0667-8] [PMID: 29940945]
[12]
Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension. Lancet Respir Med 2016; 4(4): 306-22.
[http://dx.doi.org/10.1016/S2213-2600(15)00543-3] [PMID: 26975810]
[13]
Hill NS, Cawley MJ, Heggen-Peay CL. New therapeutic paradigms and guidelines in the management of pulmonary arterial hypertension. J Manag Care Spec Pharm 2016; 22(S3): S3-S21.
[14]
Henrohn D, Björkstrand K, Lundberg JO, et al. Effects of oral supplementation with nitrate-rich beetroot juice in patients with pulmonary arterial hypertension—results from BEET-PAH, an exploratory randomized, double-blind, placebo-controlled, crossover study. J Card Fail 2018; 24(10): 640-53.
[http://dx.doi.org/10.1016/j.cardfail.2018.09.010] [PMID: 30244181]
[15]
Alves JL Jr, Gavilanes F, Jardim C, et al. Pulmonary arterial hypertension in the southern hemisphere: results from a registry of incident Brazilian cases. Chest 2015; 147(2): 495-501.
[http://dx.doi.org/10.1378/chest.14-1036] [PMID: 25317567]
[16]
Luna-López R, Ruiz Martín A, Escribano Subías P. Hipertensión arterial pulmonar. Med Clin 2022; 158(12): 622-9.
[http://dx.doi.org/10.1016/j.medcli.2022.01.003] [PMID: 35279313]
[17]
Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J 2017; 50(2): 1700889.
[http://dx.doi.org/10.1183/13993003.00889-2017] [PMID: 28775050]
[18]
Lan N, Massam B, Kulkarni S, Lang C. Pulmonary arterial hypertension: Pathophysiology and treatment. Diseases 2018; 6(2): 38.
[http://dx.doi.org/10.3390/diseases6020038] [PMID: 29772649]
[19]
Ding XF, Liang HY, Yuan B, et al. Efficacy of stem cell therapy for pulmonary arterial hypertension: A systematic review and meta-analysis of preclinical studies. Stem Cell Res Ther 2019; 10(1): 55.
[http://dx.doi.org/10.1186/s13287-019-1162-8] [PMID: 30760312]
[20]
Bourgeois A, Omura J, Habbout K, Bonnet S, Boucherat O. Pulmonary arterial hypertension: New pathophysiological insights and emerging therapeutic targets. Int J Biochem Cell Biol 2018; 104: 9-13.
[http://dx.doi.org/10.1016/j.biocel.2018.08.015] [PMID: 30189252]
[21]
Voelkel NF, Quaife RA, Leinwand LA, et al. Right ventricular function and failure: Report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 2006; 114(17): 1883-91.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.632208] [PMID: 17060398]
[22]
Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: Pulmonary arterial hypertension. Nat Rev Cardiol 2011; 8(8): 443-55.
[http://dx.doi.org/10.1038/nrcardio.2011.87] [PMID: 21691314]
[23]
de Jesus Perez VA. Molecular pathogenesis and current pathology of pulmonary hypertension. Heart Fail Rev 2016; 21(3): 239-57.
[http://dx.doi.org/10.1007/s10741-015-9519-2] [PMID: 26694808]
[24]
Tsai H, Sung YK, de Jesus PV. Recent advances in the management of pulmonary arterial hypertension. F1000 Res 2016; 5: 2755.
[http://dx.doi.org/10.12688/f1000research.9739.1] [PMID: 27990270]
[25]
Ranchoux B, Harvey LD, Ayon RJ, et al. Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series). Pulm Circ 2018; 8(1): 1-17.
[http://dx.doi.org/10.1177/2045893217752912] [PMID: 29283043]
[26]
Malenfant S, Neyron AS, Paulin R, et al. Signal transduction in the development of pulmonary arterial hypertension. Pulm Circ 2013; 3(2): 278-93.
[http://dx.doi.org/10.4103/2045-8932.114752] [PMID: 24015329]
[27]
Stenmark KR, Frid M, Perros F. Endothelial-to-Mesenchymal Transition: An Evolving Paradigm and a Promising Therapeutic Target in PAH. Circulation 2016; 133(18): 1734-7.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022479] [PMID: 27045137]
[28]
Ranchoux B, Antigny F, Rucker-Martin C, et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 2015; 131(11): 1006-18.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.008750] [PMID: 25593290]
[29]
Thenappan T, Prins KW, Pritzker MR, Scandurra J, Volmers K, Weir EK. The critical role of pulmonary arterial compliance in pulmonary hypertension. Ann Am Thorac Soc 2016; 13(2): 276-84.
[http://dx.doi.org/10.1513/AnnalsATS.201509-599FR] [PMID: 26848601]
[30]
Li G, Zhang H, Zhao L, et al. The expression of survivin in irreversible pulmonary arterial hypertension rats and its value in evaluating the reversibility of pulmonary arterial hypertension secondary to congenital heart disease. Pulm Circ 2019; 9(3): 1-11.
[http://dx.doi.org/10.1177/2045894019859480] [PMID: 31428312]
[31]
Zhang S, Liu B, Fan Z, et al. Targeted inhibition of survivin with YM155 promotes apoptosis of hypoxic human pulmonary arterial smooth muscle cells via the upregulation of voltage-dependent K+ channels. Mol Med Rep 2016; 13(4): 3415-22.
[http://dx.doi.org/10.3892/mmr.2016.4977] [PMID: 26957114]
[32]
Prieto-Lloret J, Aaronson PI. Intracellular remodelling of Ca2+ stores in pulmonary hypertension. Cardiovasc Res 2014; 103(2): 189-91.
[http://dx.doi.org/10.1093/cvr/cvu149] [PMID: 24935426]
[33]
Evans CE, Cober ND, Dai Z, Stewart DJ, Zhao YY. Endothelial cells in the pathogenesis of pulmonary arterial hypertension. Eur Respir J 2021; 58(3): 2003957.
[http://dx.doi.org/10.1183/13993003.03957-2020] [PMID: 33509961]
[34]
Guignabert C, Tu L, Girerd B, et al. New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: Importance of endothelial communication. Chest 2015; 147(2): 529-37.
[http://dx.doi.org/10.1378/chest.14-0862] [PMID: 25644906]
[35]
Vaillancourt M, Ruffenach G, Meloche J, Bonnet S. Adaptation and remodelling of the pulmonary circulation in pulmonary hypertension. Can J Cardiol 2015; 31(4): 407-15.
[http://dx.doi.org/10.1016/j.cjca.2014.10.023] [PMID: 25630876]
[36]
Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: Pathogenesis and clinical management. BMJ 2018; 360: j5492.
[http://dx.doi.org/10.1136/bmj.j5492] [PMID: 29540357]
[37]
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): H1322-31.
[http://dx.doi.org/10.1152/ajpheart.00136.2018] [PMID: 30141981]
[38]
Hemnes AR, Humbert M. Pathobiology of pulmonary arterial hypertension: Understanding the roads less travelled. Eur Respir Rev 2017; 26(146): 170093.
[http://dx.doi.org/10.1183/16000617.0093-2017] [PMID: 29263173]
[39]
Liu Y, Zhang H, Yan L, et al. MMP-2 and MMP-9 contribute to the angiogenic effect produced by hypoxia/15-HETE in pulmonary endothelial cells. J Mol Cell Cardiol 2018; 121: 36-50.
[http://dx.doi.org/10.1016/j.yjmcc.2018.06.006] [PMID: 29913136]
[40]
Schäfer M, Kheyfets VO, Schroeder JD, et al. Main pulmonary arterial wall shear stress correlates with invasive hemodynamics and stiffness in pulmonary hypertension. Pulm Circ 2016; 6(1): 37-45.
[http://dx.doi.org/10.1086/685024] [PMID: 27076906]
[41]
Dai ZK, Liu YW, Hsu JH, et al. The xanthine derivative KMUP-1 attenuates serotonin-induced vasoconstriction and K+-channel inhibitory activity via the PKC pathway in pulmonary arteries. Int J Biol Sci 2015; 11(6): 633-42.
[http://dx.doi.org/10.7150/ijbs.11127] [PMID: 25999786]
[42]
Hu Y, Chi L, Kuebler WM, Goldenberg NM. Perivascular inflammation in pulmonary arterial hypertension. Cells 2020; 9(11): 2338.
[http://dx.doi.org/10.3390/cells9112338] [PMID: 33105588]
[43]
El Kasmi KC, Pugliese SC, Riddle SR, et al. Adventitial fibroblasts induce a distinct proinflammatory/profibrotic macrophage phenotype in pulmonary hypertension. J Immunol 2014; 193(2): 597-609.
[http://dx.doi.org/10.4049/jimmunol.1303048] [PMID: 24928992]
[44]
Bello-Klein A, Mancardi D, Araujo AS, Schenkel PC, Turck P, de Lima Seolin BG. Role of redox homeostasis and inflammation in the pathogenesis of pulmonary arterial hypertension. Curr Med Chem 2018; 25(11): 1340-51.
[http://dx.doi.org/10.2174/0929867325666171226114838] [PMID: 29278203]
[45]
Gore B, Izikki M, Mercier O, et al. Key role of the endothelial TGF-β/ALK1/endoglin signaling pathway in humans and rodents pulmonary hypertension. PLoS One 2014; 9(6): e100310.
[http://dx.doi.org/10.1371/journal.pone.0100310] [PMID: 24956016]
[46]
Bofarid S, Hosman AE, Mager JJ, Snijder RJ, Post MC. Pulmonary vascular complications in hereditary hemorrhagic telangiectasia and the underlying pathophysiology. Int J Mol Sci 2021; 22(7): 3471.
[http://dx.doi.org/10.3390/ijms22073471] [PMID: 33801690]
[47]
Tatius B, Wasityastuti W, Astarini FD, Nugrahaningsih DAA. Significance of BMPR2 mutations in pulmonary arterial hypertension. Respir Investig 2021; 59(4): 397-407.
[http://dx.doi.org/10.1016/j.resinv.2021.03.011] [PMID: 34023242]
[48]
Harper RL, Reynolds AM, Bonder CS, Reynolds PN. BMPR 2 gene therapy for PAH acts via S mad and non‐ S mad signalling. Respirology 2016; 21(4): 727-33.
[http://dx.doi.org/10.1111/resp.12729] [PMID: 26809239]
[49]
Jiang Q, Liu C, Liu S, et al. Dysregulation of BMP9/BMPR2/SMAD signalling pathway contributes to pulmonary fibrosis and pulmonary hypertension induced by bleomycin in rats. Br J Pharmacol 2021; 178(1): 203-16.
[http://dx.doi.org/10.1111/bph.15285] [PMID: 33080042]
[50]
Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186(3): 261-72.
[http://dx.doi.org/10.1164/rccm.201201-0164OC] [PMID: 22679007]
[51]
Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension. Circ Res 2014; 115(1): 148-64.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.301130] [PMID: 24951764]
[52]
Alencar AKN, Cruz FF, Rocco PRM, Silva PL. Metabolic theory of pulmonary arterial hypertension: Connecting mitochondrial roles with disease control. Physiol Mini-rev 2022; 15(1): 1-11.
[53]
Dromparis P, Paulin R, Sutendra G, Qi AC, Bonnet S, Michelakis ED. Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ Res 2013; 113(2): 126-36.
[http://dx.doi.org/10.1161/CIRCRESAHA.112.300699] [PMID: 23652801]
[54]
Picard M, Shirihai OS, Gentil BJ, Burelle Y. Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am J Physiol Regul Integr Comp Physiol 2013; 304(6): R393-406.
[http://dx.doi.org/10.1152/ajpregu.00584.2012] [PMID: 23364527]
[55]
Burke PJ. Mitochondria, bioenergetics and apoptosis in cancer. Trends Cancer 2017; 3(12): 857-70.
[http://dx.doi.org/10.1016/j.trecan.2017.10.006] [PMID: 29198441]
[56]
Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369(9): 809-18.
[http://dx.doi.org/10.1056/NEJMoa1213917] [PMID: 23984728]
[57]
Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the treatment of pulmonary arterial hypertension: Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117(23): 3010-9.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.107.742510] [PMID: 18506008]
[58]
Gaine S, Chin K, Coghlan G, et al. Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. Eur Respir J 2017; 50(2): 1602493.
[http://dx.doi.org/10.1183/13993003.02493-2016] [PMID: 28818881]
[59]
Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347(5): 322-9.
[http://dx.doi.org/10.1056/NEJMoa020204] [PMID: 12151469]
[60]
Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353(20): 2148-57.
[http://dx.doi.org/10.1056/NEJMoa050010] [PMID: 16291984]
[61]
Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369(4): 330-40.
[http://dx.doi.org/10.1056/NEJMoa1209655] [PMID: 23883378]
[62]
Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med 2023; 388(16): 1478-90.
[http://dx.doi.org/10.1056/NEJMoa2213558] [PMID: 36877098]
[63]
Janssen-Cilag Farmacêutica Treatment with Uptravi® (selexipague) for adult patients with pulmonary arterial hypertension (PAH - Group I) in functional class III who did not achieve a satisfactory response with ERA and/or PDE5i, as an alternative to iloprost clinical and economic evidence dossier. Clinical and Economic Evidence Dossier 2020.
[64]
Fernandes CJ, Calderaro D, Assad APL, et al. Update on the treatment of pulmonary arterial hypertension. Arq Bras Cardiol 2021; 117(4): 750-64.
[http://dx.doi.org/10.36660/abc.20200702] [PMID: 34709302]
[65]
GlaxoSmithKline Brasil Ltda.. Volibris ®. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/volibris
[66]
Macintyre IM, Dhaun N, Goddard J, Webb DJ. Ambrisentan and its role in the management of pulmonary arterial hypertension. Drugs Today 2008; 44(12): 875-85.
[http://dx.doi.org/10.1358/dot.2008.44.12.1310761] [PMID: 19198697]
[67]
Actelion Pharmaceuticals do Brasil®. Bula Bosentana Available from: https://consultaremedios.com.br/bosentana/bula
[68]
Sidharta PN, Treiber A, Dingemanse J. Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan. Clin Pharmacokinet 2015; 54(5): 457-71.
[http://dx.doi.org/10.1007/s40262-015-0255-5] [PMID: 25860376]
[69]
Melian EB, Goa KL. Beraprost. Drugs 2002; 62(1): 107-33.
[http://dx.doi.org/10.2165/00003495-200262010-00005] [PMID: 11790158]
[70]
GlaxoSmithKline Brasil Ltda Bula Flolan Available from: https://reference.medscape.com/drug/flolan-epoprostenol-342398
[71]
Nicolas LB, Krause A, Gutierrez MM, Dingemanse J. Integrated pharmacokinetics and pharmacodynamics of epoprostenol in healthy subjects. Br J Clin Pharmacol 2012; 74(6): 978-89.
[http://dx.doi.org/10.1111/j.1365-2125.2012.04301.x] [PMID: 22515646]
[72]
Bayer AG. Bula Ilomedin Available from: https://www.bayer.com/sites/default/files/2020-11/Ventavis.pdf
[73]
Kuwana M, Abe K, Kinoshita H, et al. Efficacy, safety, and pharmacokinetics of inhaled treprostinil in Japanese patients with pulmonary arterial hypertension. Pulm Circ 2023; 13(1): e12198.
[http://dx.doi.org/10.1002/pul2.12198] [PMID: 36788940]
[74]
Frey R, Becker C, Saleh S, Unger S, van der Mey D, Mück W. Clinical pharmacokinetic and pharmacodynamic profile of riociguat. Clin Pharmacokinet 2018; 57(6): 647-61.
[http://dx.doi.org/10.1007/s40262-017-0604-7] [PMID: 29086344]
[75]
Bayer AG. Adempas® Available from: https://www.bayer.com.br/sites/bayer_com_br/files/2021-03/Bula%20Paciente_2.pdf
[76]
EMS S/A. Bula Sidenafil®. 0000. Available from: https://consultaremedios.com.br/citrato-de-sildenafila/bula
[77]
Eli Lilly Benelux S.A./N.V. Bula Cialis®. 0000. Available from: https://investor.lilly.com/news-releases/news-release-details/lilly-icos-cialis-tadalafil-makes-impressive-strides-first-six
[78]
Bayer AG. Bula Levitra Available from: https://consultaremedios.com.br/levitra/bula
[79]
Lan Z, Lv Z, Zuo W, Xiao Y. From bench to bedside: The promise of sotatercept in hematologic disorders. Biomed Pharmacother 2023; 165: 115239.
[http://dx.doi.org/10.1016/j.biopha.2023.115239] [PMID: 37516019]
[80]
Janssen-Cilag Farmacêutica LTDA. UPTRAVI Selexipag: tablet [Bula] Technical manager Erika D Rufino Medicine leaflet Available from: https://www.uptravi.com/
[81]
Janssen-Cilag International NV. Bula Opsumit®. Available from: https://consultaremedios.com.br/opsumit/bula
[82]
Seo B, Oemar BS, Siebenmann R, von Segesser L, Lüscher TF. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 1994; 89(3): 1203-8.
[http://dx.doi.org/10.1161/01.CIR.89.3.1203] [PMID: 8124808]
[83]
Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun 1994; 199(3): 1461-5.
[http://dx.doi.org/10.1006/bbrc.1994.1395] [PMID: 8147891]
[84]
de Lima-Seolin BG, Hennemann MM, Fernandes RO, et al. Bucindolol attenuates the vascular remodeling of pulmonary arteries by modulating the expression of the endothelin-1 A receptor in rats with pulmonary arterial hypertension. Biomed Pharmacother 2018; 99: 704-14.
[http://dx.doi.org/10.1016/j.biopha.2018.01.127] [PMID: 29710468]
[85]
Zimmer A, Teixeira RB, Constantin RL, et al. The progression of pulmonary arterial hypertension induced by monocrotaline is characterized by lung nitrosative and oxidative stress, and impaired pulmonary artery reactivity. Eur J Pharmacol 2021; 891: 173699.
[http://dx.doi.org/10.1016/j.ejphar.2020.173699] [PMID: 33160936]
[86]
Zancan LR, Bruinsmann FA, Paese K, et al. Oral delivery of ambrisentan-loaded lipid-core nanocapsules as a novel approach for the treatment of pulmonary arterial hypertension. Int J Pharm 2021; 610: 121181.
[http://dx.doi.org/10.1016/j.ijpharm.2021.121181] [PMID: 34653563]
[87]
Wensel R, Opitz CF, Ewert R, Bruch L, Kleber FX. Effects of iloprost inhalation on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension. Circulation 2000; 101(20): 2388-92.
[http://dx.doi.org/10.1161/01.CIR.101.20.2388] [PMID: 10821815]
[88]
Parikh V, Bhardwaj A, Nair A. Pharmacotherapy for pulmonary arterial hypertension. J Thorac Dis 2019; 11(S14): S1767-81.
[http://dx.doi.org/10.21037/jtd.2019.09.14] [PMID: 31632754]
[89]
Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012; 122(12): 4306-13.
[http://dx.doi.org/10.1172/JCI60658] [PMID: 23202738]
[90]
Yung LM, Yang P, Joshi S, et al. ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Sci Transl Med 2020; 12(543): eaaz5660.
[http://dx.doi.org/10.1126/scitranslmed.aaz5660] [PMID: 32404506]
[91]
Tielemans B, Delcroix M, Belge C, Quarck R. TGFβ and BMPRII signalling pathways in the pathogenesis of pulmonary arterial hypertension. Drug Discov Today 2019; 24(3): 703-16.
[http://dx.doi.org/10.1016/j.drudis.2018.12.001] [PMID: 30529762]
[92]
Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J 2019; 53(1): 1801899.
[http://dx.doi.org/10.1183/13993003.01899-2018] [PMID: 30545973]
[93]
Condon DF, Agarwal S, Chakraborty A, et al. Novel mechanisms targeted by drug trials in pulmonary arterial hypertension. Chest 2022; 161(4): 1060-72.
[http://dx.doi.org/10.1016/j.chest.2021.10.010] [PMID: 34655569]
[94]
Zhang Y, Alexander PB, Wang XF. TGF-β family signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol 2017; 9(4): a022145.
[http://dx.doi.org/10.1101/cshperspect.a022145] [PMID: 27920038]
[95]
Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med 2021; 384(13): 1204-15.
[http://dx.doi.org/10.1056/NEJMoa2024277] [PMID: 33789009]
[96]
Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J 2023; 61(1): 2201347.
[http://dx.doi.org/10.1183/13993003.01347-2022] [PMID: 36041750]
[97]
Waxman AB, Risbano MG, Frantz RP, Manimaran S, Lu J, Rischard F. F. D3 D003 COME TOGETHER - CLINICAL ADVANCES IN PULMONARY HYPERTENSION: LESSONS FROM BEST ABSTRACTS. American Thoracic Society 2021; A1187-7.
[http://dx.doi.org/10.1164/ajrccmconference.2021.203.1_MeetingAbstracts.A1187]
[98]
Merck & Co Merck announces positive top-line results from pivotal phase 3 STELLAR trial evaluating sotatercept for the treatment of adults with pulmonary arterial hypertension (PAH). 2022. Available from: https://www.merck.com/news/merck-announces-positive-top-line-results-from-pivotal-phase-3-stellar-trial-evaluating-sotatercept-for-the-treatment-of-adults-with-pulmonary-arterial-hypertension-pah/
[99]
Wobma H, Satwani P. Mesenchymal stromal cells: Getting ready for clinical primetime. Transfus Apheresis Sci 2021; 60(1): 103058.
[http://dx.doi.org/10.1016/j.transci.2021.103058] [PMID: 33495081]
[100]
Cruz FF, Rocco PRM. The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Rev Respir Med 2020; 14(1): 31-9.
[http://dx.doi.org/10.1080/17476348.2020.1679628] [PMID: 31608724]
[101]
Viswanathan S, Shi Y, Galipeau J, et al. Mesenchymal stem versus stromal cells: International society for cell & gene therapy (ISCT®) mesenchymal stromal cell committee position statement on nomenclature. Cytotherapy 2019; 21(10): 1019-24.
[http://dx.doi.org/10.1016/j.jcyt.2019.08.002] [PMID: 31526643]
[102]
Muhammad SA, Abbas AY, Saidu Y, Fakurazi S, Bilbis LS. Therapeutic efficacy of mesenchymal stromal cells and secretome in pulmonary arterial hypertension: A systematic review and meta-analysis. Biochimie 2020; 168: 156-68.
[http://dx.doi.org/10.1016/j.biochi.2019.10.016] [PMID: 31678635]
[103]
Noronha NC, Mizukami A, Caliári-Oliveira C, et al. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther 2019; 10(1): 131.
[http://dx.doi.org/10.1186/s13287-019-1224-y] [PMID: 31046833]
[104]
Fan XL, Zhang Y, Li X, Fu QL. Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci 2020; 77(14): 2771-94.
[http://dx.doi.org/10.1007/s00018-020-03454-6] [PMID: 31965214]
[105]
Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: Novel frontiers in regenerative medicine. Stem Cell Res Ther 2018; 9(1): 63.
[http://dx.doi.org/10.1186/s13287-018-0791-7] [PMID: 29523213]
[106]
Lötvall J, Hill AF, Hochberg F, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: A position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 2014; 3(1): 26913.
[http://dx.doi.org/10.3402/jev.v3.26913] [PMID: 25536934]
[107]
Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol 2013; 200(4): 373-83.
[http://dx.doi.org/10.1083/jcb.201211138] [PMID: 23420871]
[108]
Witwer KW, Van Balkom BWM, Bruno S, et al. Defining mesenchymal stromal cell (MSC)‐derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles 2019; 8(1): 1609206.
[http://dx.doi.org/10.1080/20013078.2019.1609206] [PMID: 31069028]
[109]
Théry C, Witwer KW, Aikawa E, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018; 7(1): 1535750.
[http://dx.doi.org/10.1080/20013078.2018.1535750] [PMID: 30637094]
[110]
Cocucci E, Meldolesi J. Ectosomes and exosomes: Shedding the confusion between extracellular vesicles. Trends Cell Biol 2015; 25(6): 364-72.
[http://dx.doi.org/10.1016/j.tcb.2015.01.004] [PMID: 25683921]
[111]
Corssac GB, Bonetto JP, Campos-Carraro C, et al. Pulmonary arterial hypertension induces the release of circulating extracellular vesicles with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats. Hypertens Res 2021; 44(8): 918-31.
[http://dx.doi.org/10.1038/s41440-021-00660-y] [PMID: 33875858]
[112]
Katsuda T, Ochiya T. Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair. Stem Cell Res Ther 2015; 6(1): 212.
[http://dx.doi.org/10.1186/s13287-015-0214-y] [PMID: 26560482]
[113]
Chen J, Hu C, Pan P. Extracellular vesicle MicroRNA transfer in lung diseases. Front Physiol 2017; 8: 1028.
[http://dx.doi.org/10.3389/fphys.2017.01028] [PMID: 29311962]
[114]
Rybak K, Robatzek S. Functions of extracellular vesicles in immunity and virulence. Plant Physiol 2019; 179(4): 1236-47.
[http://dx.doi.org/10.1104/pp.18.01557] [PMID: 30705070]
[115]
Liu Z, Liu J, Xiao M, et al. Mesenchymal stem cell-derived microvesicles alleviate pulmonary arterial hypertension by regulating renin-angiotensin system. J Am Soc Hypertens 2018; 12(6): 470-8.
[http://dx.doi.org/10.1016/j.jash.2018.02.006] [PMID: 29752040]
[116]
Klinger JR, Pereira M, Del Tatto M, et al. Mesenchymal stem cell extracellular vesicles reverse sugen/hypoxia pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2020; 62(5): 577-87.
[http://dx.doi.org/10.1165/rcmb.2019-0154OC] [PMID: 31721618]
[117]
Zhang S, Liu X, Ge LL, et al. Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling. Respir Res 2020; 21(1): 71.
[http://dx.doi.org/10.1186/s12931-020-1331-4] [PMID: 32192495]
[118]
Baek G, Choi H, Kim Y, Lee HC, Choi C. Mesenchymal stem cell-derived extracellular vesicles as therapeutics and as a drug delivery platform. Stem Cells Transl Med 2019; 8(9): 880-6.
[http://dx.doi.org/10.1002/sctm.18-0226] [PMID: 31045328]
[119]
Moloudizargari M, Asghari MH, Goel A. The therapeutic triad of extracellular vesicles: As drug targets, as drugs, and as drug carriers. Biochem Pharmacol 2021; 192: 114714.
[http://dx.doi.org/10.1016/j.bcp.2021.114714] [PMID: 34332957]
[120]
Teng F, Fussenegger M. Shedding light on extracellular vesicle biogenesis and bioengineering. Adv Sci 2021; 8(1): 2003505.
[http://dx.doi.org/10.1002/advs.202003505] [PMID: 33437589]
[121]
Miceli V, Bulati M, Iannolo G, Zito G, Gallo A, Conaldi PG. Therapeutic properties of mesenchymal stromal/stem cells: The need of cell priming for cell-free therapies in regenerative medicine. Int J Mol Sci 2021; 22(2): 763.
[http://dx.doi.org/10.3390/ijms22020763] [PMID: 33466583]
[122]
Fukumitsu M, Suzuki K. Mesenchymal stem/stromal cell therapy for pulmonary arterial hypertension: Comprehensive review of preclinical studies. J Cardiol 2019; 74(4): 304-12.
[http://dx.doi.org/10.1016/j.jjcc.2019.04.006] [PMID: 31109735]
[123]
Glassberg MK, Minkiewicz J, Toonkel RL, et al. Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER). Chest 2017; 151(5): 971-81.
[http://dx.doi.org/10.1016/j.chest.2016.10.061] [PMID: 27890713]
[124]
Baldari S, Di Rocco G, Piccoli M, Pozzobon M, Muraca M, Toietta G. Challenges and strategies for improving the regenerative effects of mesenchymal stromal cell-based therapies. Int J Mol Sci 2017; 18(10): 2087.
[http://dx.doi.org/10.3390/ijms18102087] [PMID: 28974046]
[125]
Ozaki Tan SJ, Floriano JF, Nicastro L, Emanueli C, Catapano F. Novel applications of mesenchymal stem cell-derived exosomes for myocardial infarction therapeutics. Biomolecules 2020; 10(5): 707.
[http://dx.doi.org/10.3390/biom10050707] [PMID: 32370160]
[126]
Silva LHA, Antunes MA, Dos Santos CC, Weiss DJ, Cruz FF, Rocco PRM. Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases. Stem Cell Res Ther 2018; 9(1): 45.
[http://dx.doi.org/10.1186/s13287-018-0802-8] [PMID: 29482654]
[127]
Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Gonçalves RM. Mesenchymal stromal cell secretome: Influencing therapeutic potential by cellular pre-conditioning. Front Immunol 2018; 9: 2837.
[http://dx.doi.org/10.3389/fimmu.2018.02837] [PMID: 30564236]
[128]
Sart S, Ma T, Li Y. Preconditioning stem cells for in vivo delivery. Biores Open Access 2014; 3(4): 137-49.
[http://dx.doi.org/10.1089/biores.2014.0012] [PMID: 25126478]
[129]
Deschepper M, Oudina K, David B, et al. Survival and function of mesenchymal stem cells (MSCs) depend on glucose to overcome exposure to long-term, severe and continuous hypoxia. J Cell Mol Med 2011; 15(7): 1505-14.
[http://dx.doi.org/10.1111/j.1582-4934.2010.01138.x] [PMID: 20716129]
[130]
Pattappa G, Johnstone B, Zellner J, Docheva D, Angele P. The importance of physioxia in mesenchymal stem cell chondrogenesis and the mechanisms controlling its response. Int J Mol Sci 2019; 20(3): 484.
[http://dx.doi.org/10.3390/ijms20030484] [PMID: 30678074]
[131]
Braga CL, da Silva LR, Santos RT, et al. Proteomics profile of mesenchymal stromal cells and extracellular vesicles in normoxic and hypoxic conditions. Cytotherapy 2022; 24(12): 1211-24.
[http://dx.doi.org/10.1016/j.jcyt.2022.08.009] [PMID: 36192337]
[132]
Gregorius J, Wang C, Stambouli O, et al. Small extracellular vesicles obtained from hypoxic mesenchymal stromal cells have unique characteristics that promote cerebral angiogenesis, brain remodeling and neurological recovery after focal cerebral ischemia in mice. Basic Res Cardiol 2021; 116(1): 40.
[http://dx.doi.org/10.1007/s00395-021-00881-9] [PMID: 34105014]
[133]
Anderson JD, Johansson HJ, Graham CS, et al. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappab signaling. Stem Cells 2016; 34(3): 601-13.
[http://dx.doi.org/10.1002/stem.2298] [PMID: 26782178]
[134]
Nascimento-dos-Santos G, de-Souza-Ferreira E, Lani R, et al. Neuroprotection from optic nerve injury and modulation of oxidative metabolism by transplantation of active mitochondria to the retina. Biochim Biophys Acta Mol Basis Dis 2020; 1866(5): 165686.
[http://dx.doi.org/10.1016/j.bbadis.2020.165686] [PMID: 31953215]
[135]
Roushandeh AM, Kuwahara Y, Roudkenar MH. Mitochondrial transplantation as a potential and novel master key for treatment of various incurable diseases. Cytotechnology 2019; 71(2): 647-63.
[http://dx.doi.org/10.1007/s10616-019-00302-9] [PMID: 30706303]
[136]
Nascimento-dos-Santos G, de-Souza-Ferreira E, Linden R, Galina A, Petrs-Silva H. Mitotherapy: Unraveling a promising treatment for disorders of the central nervous system and other systemic conditions. Cells 2021; 10(7): 1827.
[http://dx.doi.org/10.3390/cells10071827] [PMID: 34359994]
[137]
Liu Z, Sun Y, Qi Z, Cao L, Ding S. Mitochondrial transfer/transplantation: An emerging therapeutic approach for multiple diseases. Cell Biosci 2022; 12(1): 66.
[http://dx.doi.org/10.1186/s13578-022-00805-7] [PMID: 35590379]
[138]
Clark MA, Shay JW. Mitochondrial transformation of mammalian cells. Nature 1982; 295(5850): 605-7.
[http://dx.doi.org/10.1038/295605a0] [PMID: 7057918]
[139]
King MP, Attardi G. Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell 1988; 52(6): 811-9.
[http://dx.doi.org/10.1016/0092-8674(88)90423-0] [PMID: 3349520]
[140]
Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci 2006; 103(5): 1283-8.
[http://dx.doi.org/10.1073/pnas.0510511103] [PMID: 16432190]
[141]
McCully JD, Cowan DB, Emani SM, del Nido PJ. Mitochondrial transplantation: From animal models to clinical use in humans. Mitochondrion 2017; 34: 127-34.
[http://dx.doi.org/10.1016/j.mito.2017.03.004] [PMID: 28342934]
[142]
Shi X, Zhao M, Fu C, Fu A. Intravenous administration of mitochondria for treating experimental Parkinson’s disease. Mitochondrion 2017; 34: 91-100.
[http://dx.doi.org/10.1016/j.mito.2017.02.005] [PMID: 28242362]
[143]
Robicsek O, Ene HM, Karry R, et al. Isolated mitochondria transfer improves neuronal differentiation of schizophrenia-derived induced pluripotent stem cells and rescues deficits in a rat model of the disorder. Schizophr Bull 2018; 44(2): 432-42.
[http://dx.doi.org/10.1093/schbul/sbx077] [PMID: 28586483]
[144]
Emani SM, McCully JD. Mitochondrial transplantation: Applications for pediatric patients with congenital heart disease. Transl Pediatr 2018; 7(2): 169-75.
[http://dx.doi.org/10.21037/tp.2018.02.02] [PMID: 29770298]
[145]
Emani SM, Piekarski BL, Harrild D, del Nido PJ, McCully JD. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J Thorac Cardiovasc Surg 2017; 154(1): 286-9.
[http://dx.doi.org/10.1016/j.jtcvs.2017.02.018] [PMID: 28283239]
[146]
Zhu L, Zhang J, Zhou J, et al. Mitochondrial transplantation attenuates hypoxic pulmonary hypertension. Oncotarget 2016; 7(31): 48925-40.
[http://dx.doi.org/10.18632/oncotarget.10596] [PMID: 27419637]
[147]
Hsu CH, Roan JN, Fang SY, et al. Transplantation of viable mitochondria improves right ventricular performance and pulmonary artery remodeling in rats with pulmonary arterial hypertension. J Thorac Cardiovasc Surg 2022; 163(5): e361-73.
[http://dx.doi.org/10.1016/j.jtcvs.2020.08.014] [PMID: 32948302]
[148]
Culley MK, Chan SY. Mitochondrial metabolism in pulmonary hypertension: Beyond mountains there are mountains. J Clin Invest 2018; 128(9): 3704-15.
[http://dx.doi.org/10.1172/JCI120847] [PMID: 30080181]
[149]
Cowan DB, Yao R, Akurathi V, et al. Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One 2016; 11(8): e0160889.
[http://dx.doi.org/10.1371/journal.pone.0160889] [PMID: 27500955]

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