{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:33:56Z","timestamp":1785803636594,"version":"3.56.0"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T00:00:00Z","timestamp":1709769600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Purpose<\/jats:title>\n<jats:p>In chronic thromboembolic pulmonary hypertension (CTEPH), fibrosis of thrombi in the lumen of blood vessels and obstruction of blood vessels are important factors in the progression of the disease. Therefore, it is important to explore the key genes that lead to chronic thrombosis in order to understand the development of CTEPH, and at the same time, it is beneficial to provide new directions for early identification, disease prevention, clinical diagnosis and treatment, and development of novel therapeutic agents.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>The GSE130391 dataset was downloaded from the Gene Expression Omnibus (GEO) public database, which includes the full gene expression profiles of patients with CTEPH and Idiopathic Pulmonary Arterial Hypertension (IPAH). Differentially Expressed Genes (DEGs) of CTEPH and IPAH were screened, and then Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) functional enrichment analyses were performed on the DEGs; Weighted Gene Co-Expression Network Analysis (WGCNA) to screen the key gene modules and take the intersection genes of DEGs and the key module genes in WGCNA; STRING database was used to construct the protein-protein interaction (PPI) network; and cytoHubba analysis was performed to identify the hub genes.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>A total of 924 DEGs were screened, and the MEturquoise module with the strongest correlation was selected to take the intersection with DEGs A total of 757 intersecting genes were screened. The top ten hub genes were analyzed by cytoHubba: IL-1B, CXCL8, CCL22, CCL5, CCL20, TNF, IL-12B, JUN, EP300, and CCL4.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>IL-1B, CXCL8, CCL22, CCL5, CCL20, TNF, IL-12B, JUN, EP300, and CCL4 have diagnostic and therapeutic value in CTEPH disease, especially playing a role in chronic thrombosis. The discovery of NF-\u03baB, AP-1 transcription factors, and TNF signaling pathway through pivotal genes may be involved in the disease progression process.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0299912","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T18:33:59Z","timestamp":1709836439000},"page":"e0299912","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Analysis of genes characterizing chronic thrombosis and associated pathways in chronic thromboembolic pulmonary hypertension"],"prefix":"10.1371","volume":"19","author":[{"given":"Shizhang","family":"Zhan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenping","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9574-0376","authenticated-orcid":true,"given":"Ruoran","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"pone.0299912.ref001","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.thromres.2022.09.022","article-title":"CTEPH: A Kaiser Permanente Northern California Experience","volume":"221","author":"J Kong","year":"2023","journal-title":"Thromb Res"},{"issue":"11","key":"pone.0299912.ref002","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.3390\/medicina58111538","article-title":"Central versus Peripheral CTEPH-Clinical and Hemodynamic Specifications.","volume":"58","author":"M Kaldararova","year":"2022","journal-title":"Medicina (Kaunas)."},{"key":"pone.0299912.ref003","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1183\/09031936.00049312","article-title":"Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: A current understanding","volume":"41","author":"I.M. Lang","year":"2012","journal-title":"Eur. Respir. J"},{"key":"pone.0299912.ref004","doi-asserted-by":"crossref","first-page":"S201","DOI":"10.1513\/AnnalsATS.201509-621AS","article-title":"Chronic Thromboembolic Pulmonary Hypertension","volume":"13","author":"M. Delcroix","year":"2016","journal-title":"Epidemiology and Risk Factors. Ann. Am. Thorac. Soc"},{"key":"pone.0299912.ref005","doi-asserted-by":"crossref","first-page":"e12038","DOI":"10.1002\/pul2.12038","article-title":"Epidemiology of chronic thromboembolic pulmonary hypertension (CTEPH) in the Czech Republic.","volume":"12","author":"P. Jansa","year":"2022","journal-title":"Pulm. Circ"},{"key":"pone.0299912.ref006","doi-asserted-by":"crossref","first-page":"160112","DOI":"10.1183\/16000617.0112-2016","article-title":"The pathophysiology of chronic thromboembolic pulmonary hypertension","volume":"26","author":"G. Simonneau","year":"2017","journal-title":"Eur. Respir. Rev"},{"key":"pone.0299912.ref007","doi-asserted-by":"crossref","first-page":"106","DOI":"10.21037\/acs-2021-pte-10","article-title":"Chronic thromboembolic pulmonary hypertension: The magic of pathophysiology","volume":"11","author":"G. Simonneau","year":"2022","journal-title":"Ann. Cardiothorac. Surg"},{"key":"pone.0299912.ref008","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1183\/09031936.00169113","article-title":"Microvascular disease in chronic thromboembolic pulmonary hypertension: A role for pulmonary veins and systemic vasculature","volume":"44","author":"P. Dorfm\u00fcller","year":"2014","journal-title":"Eur. Respir. J"},{"issue":"1","key":"pone.0299912.ref009","doi-asserted-by":"crossref","first-page":"1801787","DOI":"10.1183\/13993003.01787-2018","article-title":"Limitations of resting haemodynamics in chronic thromboembolic disease without pulmonary hypertension","volume":"53","author":"EM Swietlik","year":"2019","journal-title":"Eur Respir J"},{"key":"pone.0299912.ref010","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/eurheartj\/ehv317","article-title":"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.","volume":"37","author":"N. Gali\u00e8","year":"2016","journal-title":"Heart J"},{"key":"pone.0299912.ref011","doi-asserted-by":"crossref","first-page":"1801915","DOI":"10.1183\/13993003.01915-2018","article-title":"Chronic thromboembolic pulmonary hypertension","volume":"53","author":"N.H. Kim","year":"2019","journal-title":"Eur. Respir. J"},{"issue":"4","key":"pone.0299912.ref012","doi-asserted-by":"crossref","first-page":"737","DOI":"10.3390\/cells10040737","article-title":"The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression.","volume":"10","author":"VFED Smolders","year":"2021","journal-title":"Cells."},{"issue":"2","key":"pone.0299912.ref013","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3390\/cells8020194","article-title":"Anti-Inflammatory Effect of Sulforaphane on LPS-Activated Microglia Potentially through JNK\/AP-1\/NF-\u03baB Inhibition and Nrf2\/HO-1 Activation.","volume":"8","author":"L Subedi","year":"2019","journal-title":"Cells"},{"issue":"6","key":"pone.0299912.ref014","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s10741-019-09802-4","article-title":"Research progress on the pathogenesis of CTEPH","volume":"24","author":"L Yan","year":"2019","journal-title":"Heart Fail Rev"},{"issue":"1","key":"pone.0299912.ref015","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.tcm.2016.05.010","article-title":"Update on chronic thromboembolic pulmonary hypertension","volume":"27","author":"IM Robbins","year":"2017","journal-title":"Trends Cardiovasc Med"},{"issue":"4","key":"pone.0299912.ref016","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.3390\/ijms24043979","article-title":"Pathophysiology and Treatment of Chronic Thromboembolic Pulmonary Hypertension.","volume":"24","author":"N Otani","year":"2023","journal-title":"Int J Mol Sci"},{"key":"pone.0299912.ref017","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.jtcvs.2010.11.024","article-title":"Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: Results from an international prospective registry","volume":"141","author":"E. Mayer","year":"2011","journal-title":"J. Thorac. Cardiovasc. Surg"},{"key":"pone.0299912.ref018","doi-asserted-by":"crossref","first-page":"8870","DOI":"10.1038\/s41598-020-65697-4","article-title":"Comparison of balloon pulmonary angioplasty and pulmonary vasodilator for inoperable chronic thromboembolic pulmonary hypertension: A systematic review and meta-analysis","volume":"10","author":"R. Kalra","year":"2020","journal-title":"Sci. Rep"},{"key":"pone.0299912.ref019","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1164\/rccm.200712-1841OC","article-title":"Improved outcomes in medically and surgically treated patients with chronic thromboembolic pulmonary hypertension","volume":"177","author":"R. Condliffe","year":"2008","journal-title":"Am. J. Respir. Crit Care Med"},{"key":"pone.0299912.ref020","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1080\/14017431.2016.1185532","article-title":"Characteristics and survival of adult Swedish PAH and CTEPH patients 2000\u20132014","author":"G. Radegran","year":"2016","journal-title":"Scand. Cardiovasc. J"},{"key":"pone.0299912.ref021","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1183\/13993003.00889-2017","article-title":"Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension","volume":"50","author":"A. Boucly","year":"2017","journal-title":"Eur. Respir. J"},{"key":"pone.0299912.ref022","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1183\/13993003.00589-2018","article-title":"The impact of patient choice on survival in chronic thromboembolic pulmonary hypertension","volume":"52","author":"S. R. Quadery","year":"2018","journal-title":"Eur. Respir. J"},{"key":"pone.0299912.ref023","doi-asserted-by":"crossref","first-page":"10760296211013107","DOI":"10.1177\/10760296211013107","article-title":"Upregulation of Inflammatory Cytokines in Pulmonary Embolism Using Biochip-Array Profiling.","volume":"27","author":"E Bontekoe","year":"2021","journal-title":"Clin Appl Thromb Hemost."},{"key":"pone.0299912.ref024","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cyto.2018.01.007","article-title":"Simultaneous presence of hypercoagulation and increased clot lysis time due to IL-1\u03b2, IL-6 and IL-8","volume":"110","author":"J Bester","year":"2018","journal-title":"Cytokine"},{"key":"pone.0299912.ref025","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.3389\/fphys.2020.01051","article-title":"Association Between Inflammatory Mediators and Pulmonary Blood Flow in a Rabbit Model of Acute Pulmonary Embolism Combined With Shock.","volume":"11","author":"Y Wang","year":"2020","journal-title":"Front Physiol"},{"key":"pone.0299912.ref026","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.3389\/fimmu.2019.02088","article-title":"IL-1\u03b2 Blockade Attenuates Thrombosis in a Neutrophil Extracellular Trap-Dependent Breast Cancer Model.","volume":"10","author":"T Gomes","year":"2019","journal-title":"Front Immunol"},{"issue":"18","key":"pone.0299912.ref027","doi-asserted-by":"crossref","first-page":"4763","DOI":"10.1073\/pnas.1620458114","article-title":"Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia","volume":"114","author":"N Gupta","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pone.0299912.ref028","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1172\/JCI124804","article-title":"Ectonucleotidase tri (di) phosphohydrolase-1 (ENTPD-1) disrupts inflammasome\/interleukin 1\u03b2-driven venous thrombosis","volume":"129","author":"V Yadav","year":"2019","journal-title":"J Clin Invest"},{"key":"pone.0299912.ref029","doi-asserted-by":"crossref","first-page":"104299","DOI":"10.1016\/j.ebiom.2022.104299","article-title":"Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications.","volume":"85","author":"N Potere","year":"2022","journal-title":"EBioMedicine"},{"key":"pone.0299912.ref030","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1586\/1744666X.2014.894886","article-title":"The CXCL8\/IL-8 chemokine family and its receptors in inflammatory diseases","volume":"10","author":"RC Russo","year":"2014","journal-title":"Expert Rev Clin Immunol"},{"key":"pone.0299912.ref031","doi-asserted-by":"crossref","first-page":"5051","DOI":"10.1182\/blood.V87.12.5051.bloodjournal87125051","article-title":"The proinflammatory cy-tokine response to coagulation and endotoxin in whole blood","volume":"87","author":"K. Johnson","year":"1996","journal-title":"Blood"},{"key":"pone.0299912.ref032","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.cyto.2018.01.007","article-title":"Simultaneous presence of hypercoagulation and increased clot lysis time due to IL-1\u03b2, IL-6 and IL-8","volume":"110","author":"J Bester","year":"2018","journal-title":"Cytokine"},{"key":"pone.0299912.ref033","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1111\/j.1538-7836.2004.00689.x","article-title":"Activation of innate immunity in patients with venous thrombosis: the Leiden Thrombophilia Study","volume":"2","author":"PH Reitsma","year":"2004","journal-title":"J Thromb Haemost"},{"key":"pone.0299912.ref034","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/ibd.20759","article-title":"Quantitive cytokine mRNA expression profiles in the colonic mucosa of patients with steroid naive ulcerative colitis during active and quiescent disease","volume":"15","author":"R Matsuda","year":"2009","journal-title":"Inflamm Bowel Dis"},{"issue":"11","key":"pone.0299912.ref035","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1161\/ATVBAHA.118.311660","article-title":"TNF-\u03b1 (Tumor Necrosis Factor-\u03b1).","volume":"38","author":"P Saha","year":"2018","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"2","key":"pone.0299912.ref036","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/84209","article-title":"Chemokines and disease.","volume":"2","author":"C Gerard","year":"2001","journal-title":"Nature Immunology"},{"issue":"2","key":"pone.0299912.ref037","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/84219","article-title":"Lymphocyte traffic control by chemokines","volume":"2","author":"B Moser","year":"2001","journal-title":"Nature Immunology"},{"issue":"2","key":"pone.0299912.ref038","doi-asserted-by":"crossref","first-page":"e0147958","DOI":"10.1371\/journal.pone.0147958","article-title":"The Effects of NF-\u03baB and c-Jun\/AP-1 on the Expression of Prothrombotic and Proinflammatory Molecules Induced by Anti-\u03b22GPI in Mouse.","volume":"11","author":"L Xia","year":"2016","journal-title":"PLoS One."},{"issue":"1","key":"pone.0299912.ref039","doi-asserted-by":"crossref","first-page":"18797","DOI":"10.1038\/s41598-021-98320-1","article-title":"Derivation and characterisation of endothelial cells from patients with chronic thromboembolic pulmonary hypertension","volume":"11","author":"O Tura-Ceide","year":"2021","journal-title":"Sci Rep"},{"issue":"115","key":"pone.0299912.ref040","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1183\/09059180.00007309","article-title":"Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: pathophysiology","volume":"19","author":"M. Humbert","year":"2010","journal-title":"Eur Respir Rev"},{"key":"pone.0299912.ref041","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1161\/ATVBAHA.113.302991","article-title":"Defective angiogenesis delays thrombus resolution: A potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension","volume":"34","author":"S. Alias","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol"},{"key":"pone.0299912.ref042","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1183\/09031936.00009914","article-title":"Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension","volume":"46","author":"R. Quarck","year":"2015","journal-title":"Eur. Respir. J"},{"key":"pone.0299912.ref043","first-page":"51","article-title":"Pulmonary vascular endothelium: The orchestra conductor in respiratory diseases: Highlights from basic research to therapy","author":"A. Huertas","year":"2018","journal-title":"Eur. Respir. J"},{"key":"pone.0299912.ref044","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.healun.2016.08.012","article-title":"Abnormal pulmonary endothelial cells may underlie the enigmatic pathogenesis of chronic thromboembolic pulmonary hypertension. J. heart Lung Transplant","volume":"36","author":"O. Mercier","year":"2017","journal-title":"Off. Publ. Int. Soc. Heart Transplant"},{"key":"pone.0299912.ref045","article-title":"Inflammatory cytokines regulate endothelial cell survival and tissue repair functions via NF-kappaB signaling","author":"N. Kanaji","journal-title":"J. Inflamm"},{"key":"pone.0299912.ref046","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1165\/rcmb.2013-0355OC","article-title":"Nuclear factor kappaB inhibition reduces lung vascular lumen obliteration in severe pulmonary hypertension in rats","volume":"51","author":"D. Farkas","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol"},{"issue":"4","key":"pone.0299912.ref047","doi-asserted-by":"crossref","first-page":"737","DOI":"10.3390\/cells10040737","article-title":"The Inflammatory Profile of CTEPH-Derived Endothelial Cells Is a Possible Driver of Disease Progression.","volume":"10","author":"VFED Smolders","year":"2021","journal-title":"Cells."},{"issue":"1","key":"pone.0299912.ref048","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s11239-015-1323-2","article-title":"The role of mononuclear cell tissue factor and inflammatory cytokines in patients with chronic thromboembolic pulmonary hypertension","volume":"42","author":"M Yang","year":"2016","journal-title":"J Thromb Thrombolysis"},{"issue":"1","key":"pone.0299912.ref049","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1378\/chest.126.1.135","article-title":"Cytokine response to pulmonary thromboendarterectomy","volume":"126","author":"F Langer","year":"2004","journal-title":"Chest"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0299912","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T18:34:20Z","timestamp":1709836460000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0299912"}},"subtitle":[],"editor":[{"given":"Redoy","family":"Ranjan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,3,7]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0299912","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,7]]}}}