{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:00Z","timestamp":1787028420148,"version":"build-2736575974"},"reference-count":141,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,11,23]],"date-time":"2019-11-23T00:00:00Z","timestamp":1574467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pulmonary hypertension (PH) is a potentially fatal condition with a prevalence of around 1% in the world population and most commonly caused by left heart disease (PH-LHD). Usually, in PH-LHD, the increase of pulmonary pressure is only conditioned by the retrograde transmission of the left atrial pressure. However, in some cases, the long-term retrograde pressure overload may trigger complex and irreversible biomechanical and biological changes in the pulmonary vasculature. This latter clinical entity, designated as combined pre- and post-capillary PH, is associated with very poor outcomes. The underlying mechanisms of this progression are poorly understood, and most of the current knowledge comes from the field of Group 1-PAH. Treatment is also an unsolved issue in patients with PH-LHD. Targeting the molecular pathways that regulate pulmonary hemodynamics and vascular remodeling has provided excellent results in other forms of PH but has a neutral or detrimental result in patients with PH-LHD. Therefore, a deep and comprehensive biological characterization of PH-LHD is essential to improve the diagnostic and prognostic evaluation of patients and, eventually, identify new therapeutic targets. Ongoing research is aimed at identify candidate genes, variants, non-coding RNAs, and other biomarkers with potential diagnostic and therapeutic implications. In this review, we discuss the state-of-the-art cellular, molecular, genetic, and epigenetic mechanisms potentially involved in PH-LHD. Signaling and effective pathways are particularly emphasized, as well as the current knowledge on -omic biomarkers. Our final aim is to provide readers with the biological foundations on which to ground both clinical and pre-clinical research in the field of PH-LHD.<\/jats:p>","DOI":"10.3390\/ijms20235884","type":"journal-article","created":{"date-parts":[[2019,11,25]],"date-time":"2019-11-25T03:10:00Z","timestamp":1574651400000},"page":"5884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["The Biological Bases of Group 2 Pulmonary Hypertension"],"prefix":"10.3390","volume":"20","author":[{"given":"Ana I.","family":"Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Department of Cardiology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red, CIBERCV, Instituto de Salud Carlos III, 28026 Madrid, Spain"},{"name":"Facultad de Medicine, Universidad Complutense de Madrid, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Yotti","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red, CIBERCV, Instituto de Salud Carlos III, 28026 Madrid, Spain"},{"name":"Facultad de Medicine, Universidad Complutense de Madrid, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3578-9606","authenticated-orcid":false,"given":"Ana","family":"Gonz\u00e1lez-Mansilla","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Navas-Tejedor","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red, CIBERCV, Instituto de Salud Carlos III, 28026 Madrid, Spain"},{"name":"Facultad de Medicine, Universidad Complutense de Madrid, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Chazo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria Gregorio Mara\u00f1\u00f3n, 28007 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red, CIBERCV, Instituto de 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Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Choudhary, G., Jankowich, M., and Wu, W.C. (2013). Prevalence and clinical characteristics associated with pulmonary hypertension in African-Americans. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084264"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"18022148","DOI":"10.1183\/13993003.02148-2018","article-title":"An overview of the 6th World Symposium on Pulmonary Hypertension","volume":"53","author":"Galie","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1801913","DOI":"10.1183\/13993003.01913-2018","article-title":"Haemodynamic definitions and updated clinical classification of pulmonary hypertension","volume":"53","author":"Simonneau","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/eurheartj\/ehv317","article-title":"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)","volume":"37","author":"Galie","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.jacc.2016.05.047","article-title":"Pre-capillary, combined, and post-capillary pulmonary hypertension: A pathophysiological continuum","volume":"68","author":"Opitz","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1801897","DOI":"10.1183\/13993003.01897-2018","article-title":"Pulmonary hypertension due to left heart disease","volume":"53","author":"Vachiery","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e003973","DOI":"10.1161\/CIRCOUTCOMES.117.003973","article-title":"Increasing Incidence and Prevalence of World Health Organization Groups 1 to 4 Pulmonary Hypertension: A Population-Based Cohort Study in Ontario, Canada","volume":"11","author":"Wijeratne","year":"2018","journal-title":"Circ. Cardiovasc. Qual. Outcomes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1016\/j.jacc.2016.09.942","article-title":"Clinical and biological insights into combined post- and pre-capillary pulmonary hypertension","volume":"68","author":"Assad","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","first-page":"1583","article-title":"As originally published in 1988: Long-term results of mitral valve surgery in patients with severe pulmonary hypertension. Updated in 1996","volume":"61","author":"Aris","year":"1996","journal-title":"Ann. Thorac. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1113\/JP278050","article-title":"The natural matching of harmonic responses in the pulmonary circulation","volume":"597","author":"Mombiela","year":"2019","journal-title":"J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1801877","DOI":"10.1183\/13993003.01887-2018","article-title":"Pathology and pathobiology of pulmonary hypertension: State of the art and research perspectives","volume":"53","author":"Humbert","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_13","first-page":"87","article-title":"Regulation of pulmonary vascular tone","volume":"47","author":"Barnes","year":"1995","journal-title":"Pharmacol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/S0002-9149(02)02451-7","article-title":"Usefulness of endothelin-1 concentration in capillary blood in patients with mitral stenosis as a predictor of regression of pulmonary hypertension after mitral valve replacement or valvuloplasty","volume":"90","author":"Snopek","year":"2002","journal-title":"Am. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1093\/eurheartj\/ehx751","article-title":"Aiming at the appropriate target for the treatment of pulmonary hypertension due to left heart disease","volume":"39","author":"Galie","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.jacc.2016.10.013","article-title":"Biological phenotyping of combined post-capillary and pre-capillary pulmonary hypertension: Focus on pulmonary vascular remodeling","volume":"68","author":"Leopold","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.ejheart.2004.10.021","article-title":"Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure","volume":"7","author":"Delgado","year":"2005","journal-title":"Eur. J. Heart Fail."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/cvr\/cvv047","article-title":"The role of elastic restoring forces in right-ventricular filling","volume":"107","author":"Bermejo","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jcmg.2014.12.003","article-title":"Pulmonary hypertension in valvular disease: A comprehensive review on pathophysiology to therapy from the HAVEC Group","volume":"8","author":"Magne","year":"2015","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1161\/CIRCULATIONAHA.117.031608","article-title":"Global pulmonary vascular remodeling in pulmonary hypertension associated with heart failure and preserved or reduced ejection fraction","volume":"137","author":"Fayyaz","year":"2018","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.pcad.2016.05.002","article-title":"Lung capillary stress failure and arteriolar remodelling in pulmonary hypertension associated with left heart disease (Group 2 PH)","volume":"59","author":"Dayeh","year":"2016","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1161\/HYPERTENSIONAHA.111.186072","article-title":"Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: Heart failure causes severe lung disease","volume":"59","author":"Chen","year":"2012","journal-title":"Hypertension"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1042\/CS20130296","article-title":"Lung capillary injury and repair in left heart disease: A new target for therapy?","volume":"127","author":"Azarbar","year":"2014","journal-title":"Clin. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1161\/HYPERTENSIONAHA.117.08824","article-title":"Models and molecular mechanisms of world health organization Group 2 to 4 pulmonary hypertension","volume":"71","author":"Xiong","year":"2018","journal-title":"Hypertension"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"D4","DOI":"10.1016\/j.jacc.2013.10.025","article-title":"Relevant issues in the pathology and pathobiology of pulmonary hypertension","volume":"62","author":"Tuder","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/1465-9921-10-95","article-title":"Endothelial cells and pulmonary arterial hypertension: Apoptosis, proliferation, interaction and transdifferentiation","volume":"10","author":"Sakao","year":"2009","journal-title":"Respir. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1161\/01.CIR.102.14.1718","article-title":"Secondary pulmonary hypertension in chronic heart failure: The role of the endothelium in pathophysiology and management","volume":"102","author":"Moraes","year":"2000","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2764","DOI":"10.1161\/01.CIR.101.23.2764","article-title":"Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure","volume":"101","author":"Devaux","year":"2000","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1161\/hh2401.100844","article-title":"Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: From innocent bystander to active participant","volume":"89","author":"Sartore","year":"2001","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/01.CIR.0000102381.57477.50","article-title":"Endothelial dysfunction in pulmonary hypertension","volume":"109","author":"Budhiraja","year":"2004","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/327524a0","article-title":"Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor","volume":"327","author":"Palmer","year":"1987","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.jacc.2011.12.022","article-title":"Pulmonary hypertension associated with advanced systolic heart failure: Dysregulated arginine metabolism and importance of compensatory dimethylarginine dimethylaminohydrolase-1","volume":"59","author":"Shao","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1161\/01.RES.69.4.1088","article-title":"Diminished endothelium-derived relaxing factor activity in an experimental model of chronic heart failure","volume":"69","author":"Ontkean","year":"1991","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1001\/jama.2018.14852","article-title":"Blood Institute Heart Failure Clinical Research, N. Effect of inorganic nitrite vs placebo on exercise capacity among patients with heart failure with preserved ejection fraction: The INDIE-HFpEF randomized clinical trial","volume":"320","author":"Borlaug","year":"2018","journal-title":"Jama"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/eurheartj\/ehx700","article-title":"Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: A multicenter, double-blind, randomized clinical trial","volume":"39","author":"Bermejo","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1001\/jama.2013.2024","article-title":"Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: A randomized clinical trial","volume":"309","author":"Redfield","year":"2013","journal-title":"Jama"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1161\/CIRCULATIONAHA.113.001458","article-title":"Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial Study, G., Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: A phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study","volume":"128","author":"Bonderman","year":"2013","journal-title":"Circulation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1001\/jama.2015.15734","article-title":"Investigators, S.-R., Coordinators Effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: The SOCRATES-REDUCED randomized trial","volume":"314","author":"Gheorghiade","year":"2015","journal-title":"Jama"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1093\/eurheartj\/ehw593","article-title":"Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: Results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study","volume":"38","author":"Pieske","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0002-8703(97)70105-4","article-title":"A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST)","volume":"134","author":"Califf","year":"1997","journal-title":"Am. Heart J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1161\/01.CIR.0000038497.80095.E1","article-title":"Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: The Heart Failure ET(A) Receptor Blockade Trial (HEAT)","volume":"106","author":"Luscher","year":"2002","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0140-6736(04)16723-8","article-title":"Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): Randomised, double-blind, placebo-controlled trial","volume":"364","author":"Anand","year":"2004","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cardfail.2004.05.006","article-title":"Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: Results of a pilot study","volume":"11","author":"Packer","year":"2005","journal-title":"J. Card. Fail."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1159\/000107791","article-title":"Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction, associated with secondary pulmonary hypertension--a multi-center randomized study","volume":"109","author":"Kaluski","year":"2008","journal-title":"Cardiology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.jchf.2017.02.021","article-title":"Investigators Committees Long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure: Primary results of the ENABLE Trials","volume":"5","author":"Packer","year":"2017","journal-title":"JACC Heart Fail."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1701866","DOI":"10.1183\/13993003.01886-2017","article-title":"Macitentan in pulmonary hypertension due to left ventricular dysfunction","volume":"51","author":"Vachiery","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1177\/1753465809369619","article-title":"PPARgamma as a potential therapeutic target in pulmonary hypertension","volume":"4","author":"Sutliff","year":"2010","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1067\/mtc.2001.113753","article-title":"Human angiopoietin gene expression is a marker for severity of pulmonary hypertension in patients undergoing pulmonary thromboendarterectomy","volume":"122","author":"Thistlethwaite","year":"2001","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fcvm.2018.00154","article-title":"It takes two: Endothelial-perivascular cell cross-talk in vascular development and disease","volume":"5","author":"Sweeney","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Richter, M.J., Tiede, S.L., Sommer, N., Schmidt, T., Seeger, W., Ghofrani, H.A., Schermuly, R., and Gall, H. (2016). Circulating angiopoietin-1 is not a biomarker of disease severity or prognosis in pulmonary hypertension. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165982"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1056\/NEJMoa021650","article-title":"Signaling molecules in nonfamilial pulmonary hypertension","volume":"348","author":"Du","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1136\/hrt.2004.053991","article-title":"Endothelin antagonism in pulmonary hypertension, heart failure, and beyond","volume":"91","author":"Attina","year":"2005","journal-title":"Heart"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2045893217745019","DOI":"10.1177\/2045893217745019","article-title":"The transpulmonary ratio of endothelin 1 is elevated in patients with preserved left ventricular ejection fraction and combined pre- and post-capillary pulmonary hypertension","volume":"8","author":"Meoli","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"165","DOI":"10.4103\/0975-3583.74258","article-title":"The role of RhoA\/Rho kinase pathway in endothelial dysfunction","volume":"1","author":"Yao","year":"2010","journal-title":"J. Cardiovasc. Dis. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00005-014-0310-1","article-title":"The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis","volume":"63","author":"Kowalczyk","year":"2015","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Wang, Q., Guo, Y.Z., Zhang, Y.T., Xue, J.J., Chen, Z.C., Cheng, S.Y., Ou, M.D., Cheng, K.L., and Zeng, W.J. (2016). The effects and mechanism of atorvastatin on pulmonary hypertension due to left heart disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0157171"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1101\/gad.1003302","article-title":"Guanine nucleotide exchange factors for Rho GTPases: Turning on the switch","volume":"16","author":"Schmidt","year":"2002","journal-title":"Genes Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e97","DOI":"10.1161\/ATVBAHA.116.308263","article-title":"Novel Therapeutic Targets of Pulmonary Hypertension","volume":"36","author":"Yaoita","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1002\/ppul.21323","article-title":"Attenuation of pulmonary hypertension secondary to left ventricular dysfunction in the rat by Rho-kinase inhibitor fasudil","volume":"46","author":"Dai","year":"2011","journal-title":"Pediatr. Pulmonol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3148259","DOI":"10.1155\/2018\/3148259","article-title":"Effects of Fasudil on Patients with Pulmonary Hypertension Associated with Left Ventricular Heart Failure with Preserved Ejection Fraction: A Prospective Intervention Study","volume":"2018","author":"Zhang","year":"2018","journal-title":"Can. Respir. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.biocel.2014.08.012","article-title":"Mitochondria: Roles in pulmonary hypertension","volume":"55","author":"Khoyrattee","year":"2014","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e91415","DOI":"10.1172\/jci.insight.91415","article-title":"Platelets from pulmonary hypertension patients show increased mitochondrial reserve capacity","volume":"2","author":"Nguyen","year":"2017","journal-title":"JCI Insight"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"H570","DOI":"10.1152\/ajpheart.01324.2007","article-title":"Mitochondrial metabolism, redox signaling, and fusion: A mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer","volume":"294","author":"Archer","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1164\/rccm.201108-1536PP","article-title":"Targeting energetic metabolism: A new frontier in the pathogenesis and treatment of pulmonary hypertension","volume":"185","author":"Tuder","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Nguyen, Q.L., Wang, Y., Helbling, N., Simon, M.A., and Shiva, S. (2019). Alterations in platelet bioenergetics in Group 2 PH-HFpEF patients. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220490"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2464S","DOI":"10.1093\/jn\/134.9.2464S","article-title":"Fatty acid binding proteins--the evolutionary crossroads of inflammatory and metabolic responses","volume":"134","author":"Makowski","year":"2004","journal-title":"J. Nutr."},{"key":"ref_67","first-page":"30293","article-title":"Analysis of novel cardiovascular biomarkers in patients with pulmonary hypertension (PH)","volume":"S1443-9506","author":"Mirna","year":"2019","journal-title":"Heart Lung Circ."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1002\/cphy.c120024","article-title":"Reactive oxygen species in pulmonary vascular remodeling","volume":"3","author":"Aggarwal","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1093\/ajh\/hpt292","article-title":"Molecular characterization of reactive oxygen species in systemic and pulmonary hypertension","volume":"27","author":"Zuo","year":"2014","journal-title":"Am. J. Hypertens."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1089\/ars.2018.7699","article-title":"Redox regulation of ion channels and receptors in pulmonary hypertension","volume":"31","author":"Resta","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Lambert, M., Capuano, V., Olschewski, A., Sabourin, J., Nagaraj, C., Girerd, B., Weatherald, J., Humbert, M., and Antigny, F. (2018). Ion channels in pulmonary hypertension: A therapeutic interest?. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103162"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1537-1891(02)00123-4","article-title":"Role of K+ channels in pulmonary hypertension","volume":"38","author":"Mandegar","year":"2002","journal-title":"Vascul. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/HYPERTENSIONAHA.119.12992","article-title":"Pulmonary hypertension and ATP-sensitive potassium channels","volume":"74","author":"McClenaghan","year":"2019","journal-title":"Hypertension"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1093\/cvr\/3.4.467","article-title":"Pulmonary mast cells in mitral stenosis","volume":"3","author":"Heath","year":"1969","journal-title":"Cardiovasc. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2045893218757596","DOI":"10.1177\/2045893218757596","article-title":"Inflammation and autoimmunity in pulmonary hypertension: Is there a role for endothelial adhesion molecules? (2017 Grover Conference Series)","volume":"8","author":"Kuebler","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1164\/rccm.201202-0335OC","article-title":"Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension","volume":"186","author":"Savai","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.carpath.2004.06.003","article-title":"Decreased numbers of T-lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts","volume":"13","author":"Pinto","year":"2004","journal-title":"Cardiovasc. Pathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"L710","DOI":"10.1152\/ajplung.00311.2016","article-title":"The mast cell-B cell axis in lung vascular remodeling and pulmonary hypertension","volume":"312","author":"Breitling","year":"2017","journal-title":"Am. J. Physiol. Lung. Cell Mol. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1161\/CIRCRESAHA.118.314555","article-title":"Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease","volume":"125","author":"Ranchoux","year":"2019","journal-title":"Circ. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1164\/rccm.200811-1678OC","article-title":"Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension","volume":"179","author":"Ferreira","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"903","DOI":"10.33549\/physiolres.931278","article-title":"In vitro hypoxia increases production of matrix metalloproteinases and tryptase in isolated rat lung mast cells","volume":"57","author":"Maxova","year":"2008","journal-title":"Physiol. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4045","DOI":"10.4049\/jimmunol.170.8.4045","article-title":"Regulation of activin A expression in mast cells and asthma: Its effect on the proliferation of human airway smooth muscle cells","volume":"170","author":"Cho","year":"2003","journal-title":"J. Immunol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1183\/09031936.00043310","article-title":"Mast cells promote lung vascular remodelling in pulmonary hypertension","volume":"37","author":"Hoffmann","year":"2011","journal-title":"Eur. Respir. J."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/path.4833","article-title":"The role of genetics in pulmonary arterial hypertension","volume":"241","author":"Ma","year":"2017","journal-title":"J. Pathol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1097\/MCP.0000000000000414","article-title":"Genetics of pulmonary hypertension in the clinic","volume":"23","author":"Girerd","year":"2017","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Garcia-Rivas, G., Jerjes-Sanchez, C., Rodriguez, D., Garcia-Pelaez, J., and Trevino, V. (2017). A systematic review of genetic mutations in pulmonary arterial hypertension. BMC Med. Genet., 18.","DOI":"10.1186\/s12881-017-0440-5"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Southgate, L., Machado, R.D., Graf, S., and Morrell, N.W. (2019). Molecular genetic framework underlying pulmonary arterial hypertension. Nat. Rev. Cardiol.","DOI":"10.1038\/s41569-019-0242-x"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S2213-2600(18)30409-0","article-title":"Genetic determinants of risk in pulmonary arterial hypertension: International genome-wide association studies and meta-analysis","volume":"7","author":"Rhodes","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1801899","DOI":"10.1183\/13993003.01899-2018","article-title":"Genetics and genomics of pulmonary arterial hypertension","volume":"53","author":"Morrell","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Tian, W., Jiang, X., Sung, Y.K., Shuffle, E., Wu, T.H., Kao, P.N., Tu, A.B., Dorfmuller, P., Cao, A., and Wang, L. (2019). Phenotypically-silent bone morphogenetic protein receptor 2 (BMPR2) mutations predispose rats to inflammation-induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. Circulation.","DOI":"10.1161\/CIRCULATIONAHA.119.040629"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Andruska, A., and Spiekerkoetter, E. (2018). Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: Contributions to pulmonary arterial hypertension. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092499"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1016\/j.jacc.2009.04.015","article-title":"Genetics and genomics of pulmonary arterial hypertension","volume":"54","author":"Machado","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1086\/316947","article-title":"BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension","volume":"68","author":"Machado","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1161\/CIRCRESAHA.115.303404","article-title":"The genetics of pulmonary arterial hypertension","volume":"115","author":"Austin","year":"2014","journal-title":"Circ. Res."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"West, J., Cogan, J., Geraci, M., Robinson, L., Newman, J., Phillips, J.A., Lane, K., Meyrick, B., and Loyd, J. (2008). Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med. Genom., 1.","DOI":"10.1186\/1755-8794-1-45"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Gore, B., Izikki, M., Mercier, O., Dewachter, L., Fadel, E., Humbert, M., Dartevelle, P., Simonneau, G., Naeije, R., and Lebrin, F. (2014). Key role of the endothelial TGF-beta\/ALK1\/endoglin signaling pathway in humans and rodents pulmonary hypertension. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100310"},{"key":"ref_97","first-page":"2071","article-title":"Analysis of genetic mutation and modifier genes in pulmonary arterial hypertension","volume":"66","author":"Fujiwara","year":"2008","journal-title":"Nihon Rinsho"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1253\/circj.72.127","article-title":"Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension","volume":"72","author":"Fujiwara","year":"2008","journal-title":"Circ. J."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.recesp.2016.03.031","article-title":"Molecular analysis of BMPR2, TBX4, and KCNK3 and genotype-phenotype correlations in spanish patients and families with idiopathic and hereditary pulmonary arterial hypertension","volume":"69","author":"Navas","year":"2016","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1164\/ajrccm.162.4.9909120","article-title":"Deletion polymorphisms in the angiotensin converting enzyme gene are associated with pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease","volume":"162","author":"Kanazawa","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Pousada, G., Baloira, A., Vilarino, C., Cifrian, J.M., and Valverde, D. (2014). Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100261"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1164\/rccm.200509-1365OC","article-title":"Genetic association of the serotonin transporter in pulmonary arterial hypertension","volume":"173","author":"Machado","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.cardiores.2003.09.015","article-title":"Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension","volume":"60","author":"Blanpain","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e002087","DOI":"10.1161\/CIRCGEN.118.002087","article-title":"Loss-of-function ABCC8 mutations in pulmonary arterial hypertension","volume":"11","author":"Bohnen","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Opitz, I., and Kirschner, M.B. (2019). Molecular research in chronic thromboembolic pulmonary hypertension. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030784"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Vorselaars, V.M.M., Hosman, A.E., Westermann, C.J.J., Snijder, R.J., Mager, J.J., Goumans, M.-J., and Post, M.C. (2018). Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103203"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1159\/000250322","article-title":"Sequence variants in BMPR2 and genes involved in the serotonin and nitric oxide pathways in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Relation to clinical parameters and comparison with left heart disease","volume":"79","author":"Ulrich","year":"2010","journal-title":"Respiration"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"262","DOI":"10.5114\/aoms.2017.68938","article-title":"Pulmonary hypertension in left heart disease","volume":"15","author":"Mehra","year":"2019","journal-title":"Arch. Med. Sci."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"157","DOI":"10.3389\/fmed.2018.00157","article-title":"Using omics to understand and treat pulmonary vascular disease","volume":"5","author":"Hemnes","year":"2018","journal-title":"Front. Med."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Yin, C., Li, K., Yu, Y., Huang, H., Yu, Y., Wang, Z., Yan, J., Pu, Y., Li, Z., and Li, D. (2018). Genome-wide association study identifies loci and candidate genes for non-idiopathic pulmonary hypertension in Eastern Chinese Han population. BMC Pulm. Med., 18.","DOI":"10.1186\/s12890-018-0719-0"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2045894018773049","DOI":"10.1177\/2045894018773049","article-title":"Endothelial nitric oxide synthase genotype is associated with pulmonary hypertension severity in left heart failure patients","volume":"8","author":"Duarte","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.ahj.2006.12.011","article-title":"Repeat length polymorphism of the serotonin transporter gene influences pulmonary artery pressure in heart failure","volume":"153","author":"Olson","year":"2007","journal-title":"Am. Heart J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1086\/688516","article-title":"Hemodynamic evidence of vascular remodeling in combined post- and precapillary pulmonary hypertension","volume":"6","author":"Assad","year":"2016","journal-title":"Pulm. Circ."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1164\/rccm.201409-1742OC","article-title":"Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension","volume":"191","author":"Damico","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1161\/CIRCRESAHA.111.263848","article-title":"Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension","volume":"110","author":"Marsboom","year":"2012","journal-title":"Circ. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1183\/13993003.01714-2015","article-title":"The emerging role of epigenetics in pulmonary hypertension","volume":"48","author":"Gamen","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1161\/CIRCULATIONAHA.109.916098","article-title":"Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: A basis for excessive cell proliferation and a new therapeutic target","volume":"121","author":"Archer","year":"2010","journal-title":"Circulation"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2042","DOI":"10.1056\/NEJMra050002","article-title":"Acute oxygen-sensing mechanisms","volume":"353","author":"Weir","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"L1001","DOI":"10.1152\/ajplung.00092.2012","article-title":"Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: Role of histone acetylation","volume":"303","author":"Yang","year":"2012","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"52995","DOI":"10.18632\/oncotarget.18031","article-title":"Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension","volume":"8","author":"Hautefort","year":"2017","journal-title":"Oncotarget"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1164\/rccm.201208-1364OC","article-title":"Cytotoxic cells and granulysin in pulmonary arterial hypertension and pulmonary veno-occlusive disease","volume":"187","author":"Perros","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1097\/HJH.0b013e32833e08f1","article-title":"Epigenetic regulation of the endothelial nitric oxide synthase gene in persistent pulmonary hypertension of the newborn rat","volume":"28","author":"Xu","year":"2010","journal-title":"J. Hypertens."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.4049\/jimmunol.1100479","article-title":"Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension","volume":"187","author":"Li","year":"2011","journal-title":"J. Immunol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.cmet.2014.08.011","article-title":"Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans","volume":"20","author":"Paulin","year":"2014","journal-title":"Cell Metab."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Aljubran, S.A., Cox, R., Tamarapu Parthasarathy, P., Kollongod Ramanathan, G., Rajanbabu, V., Bao, H., Mohapatra, S.S., Lockey, R., and Kolliputi, N. (2012). Enhancer of zeste homolog 2 induces pulmonary artery smooth muscle cell proliferation. PLoS ONE, 7.","DOI":"10.1371\/annotation\/8580b50a-1556-4c86-aeb6-a88af839297a"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1007\/s00109-011-0788-5","article-title":"From oncoproteins\/tumor suppressors to microRNAs, the newest therapeutic targets for pulmonary arterial hypertension","volume":"89","author":"Paulin","year":"2011","journal-title":"J. Mol. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"278","DOI":"10.4103\/2045-8932.101395","article-title":"Holding our breath: The emerging and anticipated roles of microRNA in pulmonary hypertension","volume":"2","author":"White","year":"2012","journal-title":"Pulm. Circ."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1164\/rccm.201304-0672RR","article-title":"High-frequency oscillatory ventilation, microRNAs in pulmonary hypertension, and gastric residual volumes","volume":"188","author":"Krick","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.arcmed.2013.08.003","article-title":"Pulmonary arterial hypertension and microRNAs--an ever-growing partnership","volume":"44","author":"Wang","year":"2013","journal-title":"Arch. Med. Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2883","DOI":"10.1007\/s11033-018-4335-0","article-title":"Recent research progress of microRNAs in hypertension pathogenesis, with a focus on the roles of miRNAs in pulmonary arterial hypertension","volume":"45","author":"Miao","year":"2018","journal-title":"Mol. Biol. Rep."},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Bertero, T., Handen, A.L., and Chan, S.Y. (2018). Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130\/301-Vascular Matrix Feedback Loop. Int. J. Mol..Sci., 19.","DOI":"10.3390\/ijms19082289"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"L861","DOI":"10.1152\/ajplung.00201.2010","article-title":"MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration","volume":"299","author":"Sarkar","year":"2010","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1161\/CIRCRESAHA.109.197491","article-title":"Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17\/92 pathway","volume":"104","author":"Brock","year":"2009","journal-title":"Circ. Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1084\/jem.20101812","article-title":"Role for miR-204 in human pulmonary arterial hypertension","volume":"208","author":"Courboulin","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_135","first-page":"98","article-title":"Expression of Let-7 family microRNAs in skin correlates negatively with severity of pulmonary hypertension in patients with systemic scleroderma","volume":"8","author":"Izumiya","year":"2015","journal-title":"Int. J. Cardiol. Heart Vasc."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2045894019840646","DOI":"10.1177\/2045894019840646","article-title":"Distinct plasma gradients of microRNA-204 in the pulmonary circulation of patients suffering from WHO Groups I and II pulmonary hypertension","volume":"9","author":"Estephan","year":"2019","journal-title":"Pulm. Circ."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1159\/000475569","article-title":"The circulating microRNA-206 level predicts the severity of pulmonary hypertension in patients with left heart diseases","volume":"41","author":"Jin","year":"2017","journal-title":"Cell Physiol. Biochem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13059-019-1629-z","article-title":"Prediction of functional microRNA targets by integrative modeling of microRNA binding and target expression data","volume":"20","author":"Liu","year":"2019","journal-title":"Genome Biol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"e91327","DOI":"10.1172\/jci.insight.91327","article-title":"Discerning functional hierarchies of microRNAs in pulmonary hypertension","volume":"2","author":"Negi","year":"2017","journal-title":"JCI Insight"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1177\/2045893217704206","article-title":"Assessment of microRNA and gene dysregulation in pulmonary hypertension by endoarterial biopsy","volume":"7","author":"Rothman","year":"2017","journal-title":"Pulm. 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