{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T17:17:06Z","timestamp":1784567826862,"version":"3.55.0"},"reference-count":26,"publisher":"European Respiratory Society (ERS)","issue":"1","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2016-I2M-4-003"],"award-info":[{"award-number":["2016-I2M-4-003"]}]},{"name":"National Key Research and Development Program of China","award":["2016YFA0102300"],"award-info":[{"award-number":["2016YFA0102300"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870051, 81670054"],"award-info":[{"award-number":["81870051, 81670054"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2021,11,10]]},"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Mutations in bone morphogenetic protein type II receptor (<jats:italic>BMPR2<\/jats:italic>) have been found in patients with congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH). Our study aimed to clarify whether deficient BMPR2 signalling acts through downstream effectors, inhibitors of DNA-binding proteins (IDs) during heart development to contribute to the progress of PAH in CHD patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To confirm that IDs are downstream effectors of BMPR2 signalling in cardiac mesoderm progenitors (CMPs) and contribute to PAH, we generated cardiomyocyte-specific<jats:italic>Id 1\/3<\/jats:italic>knockout mice (Ids cDKO), and 12 out of 25 developed mild PAH with altered haemodynamic indices and pulmonary vascular remodelling. Moreover, we generated<jats:italic>ID1<\/jats:italic>and<jats:italic>ID3<\/jats:italic>double-knockout (IDs KO) human embryonic stem cells that recapitulated the BMPR2 signalling deficiency of CHD-PAH induced pluripotent stem cells (iPSCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cardiomyocytes differentiated from iPSCs derived from CHD-PAH patients with BMP receptor mutations exhibited dysfunctional cardiac differentiation and reduced calcium (Ca<jats:sup>2+<\/jats:sup>) transients, as evidenced by confocal microscopy experiments. Smad1\/5 phosphorylation and ID1 and ID3 expression were reduced in CHD-PAH iPSCs and in<jats:italic>Bmpr2<\/jats:italic><jats:sup>+\/\u2013<\/jats:sup>rat right ventricles. Moreover, ultrasound revealed that 33% of Ids cDKO mice had detectable defects in their ventricular septum and pulmonary regurgitation. Cardiomyocytes isolated from mouse right ventricles also showed reduced Ca<jats:sup>2+<\/jats:sup>transients and shortened sarcomeres. Single-cell RNA sequencing analysis revealed impaired differentiation of CMPs and downregulated USP9X expression in IDs KO cells compared with wild-type cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We found that BMPR2 signals through IDs and USP9X to regulate cardiac differentiation, and the loss of ID1 and ID3 expression contributes to cardiomyocyte dysfunction in CHD-PAH patients with<jats:italic>BMPR2<\/jats:italic>mutations.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.00327-2021","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T14:23:18Z","timestamp":1638454998000},"page":"2100327","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Single-cell RNA sequencing reveals that<i>BMPR2<\/i>mutation regulates right ventricular function<i>via ID<\/i>genes"],"prefix":"10.1183","volume":"60","author":[{"given":"Mingxia","family":"Du","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Piao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoqiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Perros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas W.","family":"Morrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9715-8100","authenticated-orcid":false,"given":"Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"2024102102460540000_60.1.2100327.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13167-4"},{"key":"2024102102460540000_60.1.2100327.2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.F307"},{"key":"2024102102460540000_60.1.2100327.3","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.04.00018604"},{"key":"2024102102460540000_60.1.2100327.4","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ijcard.2016.02.150","article-title":"BMPR2 mutation is a potential predisposing genetic risk factor for congenital heart disease associated pulmonary vascular disease","volume":"211","author":"Liu","year":"2016","journal-title":"Int J Cardiol"},{"key":"2024102102460540000_60.1.2100327.5","doi-asserted-by":"publisher","DOI":"10.1161\/hc3201.094152"},{"key":"2024102102460540000_60.1.2100327.6","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3877"},{"key":"2024102102460540000_60.1.2100327.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2009.04.032"},{"key":"2024102102460540000_60.1.2100327.8","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1161\/CIRCULATIONAHA.118.033744","article-title":"Bmpr2 mutant rats develop pulmonary and cardiac characteristics of pulmonary arterial hypertension","volume":"139","author":"Hautefort","year":"2019","journal-title":"Circulation"},{"key":"2024102102460540000_60.1.2100327.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.10.004"},{"key":"2024102102460540000_60.1.2100327.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.1102612"},{"key":"2024102102460540000_60.1.2100327.11","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu215"},{"key":"2024102102460540000_60.1.2100327.12","doi-asserted-by":"publisher","DOI":"10.1101\/gad.300400.117"},{"key":"2024102102460540000_60.1.2100327.13","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2011.12"},{"key":"2024102102460540000_60.1.2100327.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02456-y"},{"key":"2024102102460540000_60.1.2100327.15","doi-asserted-by":"publisher","DOI":"10.1242\/dev.004432"},{"key":"2024102102460540000_60.1.2100327.16","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1124803"},{"key":"2024102102460540000_60.1.2100327.17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.28.19838"},{"key":"2024102102460540000_60.1.2100327.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00847-X"},{"key":"2024102102460540000_60.1.2100327.19","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/jnc.12999","article-title":"Identification","volume":"132","author":"Yamasaki","year":"2015","journal-title":"J Neurochem"},{"key":"2024102102460540000_60.1.2100327.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.12.015"},{"key":"2024102102460540000_60.1.2100327.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2011.06.015"},{"key":"2024102102460540000_60.1.2100327.22","doi-asserted-by":"publisher","DOI":"10.1038\/nature18633"},{"key":"2024102102460540000_60.1.2100327.23","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201906-1141OC"},{"key":"2024102102460540000_60.1.2100327.24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.9.5801"},{"key":"2024102102460540000_60.1.2100327.25","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02229-2017"},{"key":"2024102102460540000_60.1.2100327.26","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1161\/CIRCULATIONAHA.119.040629","article-title":"Phenotypically silent bone morphogenetic protein receptor 2 mutations predispose rats to inflammation-induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation","volume":"140","author":"Tian","year":"2019","journal-title":"Circulation"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.00327-2021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:21:14Z","timestamp":1740378074000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.00327-2021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,7,7]]},"published-print":{"date-parts":[[2022,7]]}},"alternative-id":["10.1183\/13993003.00327-2021"],"URL":"https:\/\/doi.org\/10.1183\/13993003.00327-2021","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,2]]}}}