{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:48:54Z","timestamp":1789069734142,"version":"build-2803163510"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,2,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>BACKGROUND<\/jats:title>\n            <jats:p xml:lang=\"en\">Pulmonary arterial hypertension (PAH) is an incurable disease initiated by endothelial dysfunction, secondary to vascular inflammation and occlusive pulmonary arterial vascular remodeling, resulting in elevated pulmonary arterial pressure and right heart failure. Previous research has reported that dysfunction of type 2 bone morphogenetic protein receptor (BMPR2) signaling pathway in endothelium is inclined to prompt inflammation in PAH models, but the underlying mechanism of BMPR2 deficiency\u2010mediated inflammation needs further investigation. This study was designed to investigate whether BMPR2 deficiency contributes to pulmonary arterial hypertension via the NLRP3 (NOD\u2010like receptor family protein 3)\/GSDME (gasdermin E)\u2010mediated pyroptosis pathway.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>METHODS AND RESULTS<\/jats:title>\n            <jats:p xml:lang=\"en\">NLRP3 knockout or short hairpin RNA interference of GSDME was performed in PAH animal models to investigate its effect on PAH progression. In addition, the effects of BMPR2 deficiency and restoration of BMPR2 by BMP9 (bone morphogenetic protein 9) or FK506 on pyroptosis were explored both in animal and cell models. Knockout of NLRP3 or short hairpin RNA interference of GSDME in animal models can alleviate the development of pyroptosis, accompanied with improved endothelial integrity, vascular remodeling, and right ventricular systolic pressure. Blocking BMPR2 is sufficient to induce NLRP3 upregulation and release of inflammatory factor IL\u20101\u03b2 (interleukin\u20101\u03b2) in pulmonary arterial endothelial cells. Moreover, BMPR2 deficiency can induce GSDME\u2010mediated pyroptosis through NLRP3 activation in 2 animal models, whereas activation of BMPR2 signaling by FK506 or BMP9 can reverse these phenotypes.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>CONCLUSIONS<\/jats:title>\n            <jats:p xml:lang=\"en\">These findings provide evidence that loss of BMPR2 signaling promotes endothelial cell pyroptosis by enhancing NLRP3\/GSDME signaling in PAH. Our findings may provide new insights to explore the inflammatory mechanism of PAH treatment.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.034726","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T11:15:00Z","timestamp":1737630900000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":13,"title":["Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD\u2010Like Receptor Family Protein 3\/Gasdermin E\u2010Mediated Pyroptosis in Pulmonary Arterial\u00a0Hypertension"],"prefix":"10.1161","volume":"14","author":[{"given":"Xiao\u2010ting","family":"Tian","sequence":"first","affiliation":[{"name":"The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan China"},{"name":"Department of Pharmacology, Xiangya School of Pharmaceutical Science Central South University Changsha China"},{"name":"Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou\u2010yang\u2010fan","family":"Peng","sequence":"additional","affiliation":[{"name":"The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan China"},{"name":"Department of Health Management Center, The Third Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010si","family":"Wu","sequence":"additional","affiliation":[{"name":"The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan China"},{"name":"Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan, School of Medicine Hunan Normal University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan\u2010yuan","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Xiangya School of Pharmaceutical Science Central South University Changsha China"},{"name":"Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010chun","family":"Li","sequence":"additional","affiliation":[{"name":"Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples Changsha China"},{"name":"Department of Health Management Center, The Third Xiangya Hospital Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u2010Yuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Xiangya Nursing School Central South University Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9792-0916","authenticated-orcid":false,"given":"Alex F.","family":"Chen","sequence":"additional","affiliation":[{"name":"The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan China"},{"name":"Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0624-8811","authenticated-orcid":false,"given":"Xiao\u2010hui","family":"Li","sequence":"additional","affiliation":[{"name":"The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan China"},{"name":"Department of Pharmacology, Xiangya School of Pharmaceutical Science Central South University Changsha China"},{"name":"Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/2045893217752912"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000166926.54293.68"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2016.10.047"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9398"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1177\/2045894018765840"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3877"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65592"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.179960"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301141"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.301313"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14079"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2012.07.006"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201408-1509OC"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2018.12.006"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S51250"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2016.10.004"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2017.05.005"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature18590"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14128"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.121.17868"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201911303"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2018.1001"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2020.03.044"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007446"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802696"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.4HI0320-028R"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-018-0780-0"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature15514"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22393"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2017.11.005"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.117138"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2018.9427"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00158.2018"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-016-1899-1"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033744"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.141200"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100851RR"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcha.2024.101569"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.034726","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T11:00:53Z","timestamp":1738666853000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.034726"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,4]]},"references-count":38,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,2,4]]}},"alternative-id":["10.1161\/JAHA.124.034726"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.034726","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,4]]},"assertion":[{"value":"2024-01-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e034726"}}