{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T09:42:46Z","timestamp":1793785366693,"version":"4.6.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Science, Sports, and Culture of Japan","doi-asserted-by":"crossref","award":["20K16854"],"award-info":[{"award-number":["20K16854"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Science, Sports, and Culture of Japan","doi-asserted-by":"crossref","award":["17K16261"],"award-info":[{"award-number":["17K16261"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were significantly increased, and angiogenesis and oxygen consumption rate (OCR) were significantly impaired as compared with cDi21-iPSC-derived ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was significantly upregulated in T21-ECs. Both EGR1 suppression by siRNA and pharmacological inhibitor could recover the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Alternately, the study also revealed that DYRK1A was responsible to increase EGR1 expression via PPARG suppression, and that chemical inhibition of DYRK1A could restore the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Finally, we demonstrated that EGR1 was significantly upregulated in the pulmonary arterial ECs from lung specimens of a patient with DS and PAH. In conclusion, DYRK1A\/PPARG\/EGR1 pathway could play a central role for the pulmonary EC functions and thus be associated with the pathogenesis of PAH in DS.<\/jats:p>","DOI":"10.1093\/hmg\/ddad162","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T17:38:51Z","timestamp":1696441131000},"page":"78-90","source":"Crossref","is-referenced-by-count":12,"title":["Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify <i>DYRK1A\/PPARG\/EGR1<\/i> pathway is responsible for Down syndrome-associated pulmonary hypertension"],"prefix":"10.1093","volume":"33","author":[{"given":"Hidehiro","family":"Suginobe","sequence":"first","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidekazu","family":"Ishida","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichiro","family":"Ishii","sequence":"additional","affiliation":[{"name":"Osaka Children\u2019s and Women\u2019s Hospital Department of Pediatric Cardiology, , 840 Murodohcho, Izumi, Osaka 594-1101 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutoshi","family":"Ueda","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chika","family":"Yoshihara","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Ueyama","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renjie","family":"Wang","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Tsuru","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"},{"name":"Niigata University School of Medicine Department of Pediatrics, , 1-757 Asahimachi-dori, chuo-ku, Niigata 951-8510 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Hirose","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Ishii","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Narita","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuji","family":"Kitabatake","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Ozono","sequence":"additional","affiliation":[{"name":"Osaka University Graduate School of Medicine Department of Pediatrics, , 2-2 Yamadaoka, Suita, Osaka 565-0871 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"2023121917034489900_ref1","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/j.jpeds.2013.06.013","article-title":"Current estimate of Down syndrome population prevalence in the United States","volume":"163","author":"Presson","year":"2013","journal-title":"J Pediatr"},{"key":"2023121917034489900_ref2","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1111\/j.1651-2227.1993.tb12763.x","article-title":"Pulmonary vascular resistance in complete atrioventricular septal defect. 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