Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension

Suginobe, Hidehiro; Ishida, Hidekazu; Ishii, Yoichiro; Ueda, Kazutoshi; Yoshihara, Chika; Ueyama, Atsuko; Wang, Renjie; Tsuru, Hirofumi; Hashimoto, Kazuhisa; Hirose, Masaki; Ishii, Ryo; Narita, Jun; Kitabatake, Yasuji; Ozono, Keiichi

doi:https://doi.org/10.1093/hmg/ddad162

Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension

Suginobe, Hidehiro; Ishida, Hidekazu; Ishii, Yoichiro et al.

Human Molecular Genetics, 2023, 163, 1163

Number of Access:1,570（2025-07-22 20:42 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/93230

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Title	Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension
Creator	CreatorName Suginobe, Hidehiro
	NRID 1000050467552 1000050467552 researchmap permalink researcher_cardio researcher_cardio Scopus Author ID 36863872000 36863872000 CreatorName Ishida, Hidekazu
	NRID 1000090573882 1000090573882 CreatorName Ishii, Yoichiro
	CreatorName Ueda, Kazutoshi
	CreatorName Yoshihara, Chika
	CreatorName Ueyama, Atsuko
	CreatorName Wang, Renjie
	CreatorName Tsuru, Hirofumi
	CreatorName Hashimoto, Kazuhisa
	researchmap permalink masahirose masahirose Scopus Author ID 57908743200 57908743200 NRID 1000010973662 1000010973662 CreatorName Hirose, Masaki
	NRID 1000090794008 1000090794008 researchmap permalink iryo-0918 iryo-0918 Scopus Author ID 56017974100 56017974100 CreatorName Ishii, Ryo
	NRID 1000070467562 1000070467562 researchmap permalink J-narita J-narita Scopus Author ID 36993204400 36993204400 CreatorName Narita, Jun
	NRID 1000080506494 1000080506494 ORCID 0000-0002-2907-9512 0000-0002-2907-9512 researchmap permalink kyasuji kyasuji Scopus Author ID 7003894272 7003894272 CreatorName Kitabatake, Yasuji
	NRID 1000020270770 1000020270770 researchmap permalink read0092357 read0092357 Scopus Author ID 55545335700 55545335700 CreatorName Ozono, Keiichi
Subject	induced pluripotent stem cell
	Down syndrome ;endothelialcell
	endothelial cell
	EGR1
	pulmonaryhypertension
Description	Suginobe Hidehiro, Ishida Hidekazu, Ishii Yoichiro, et al. Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension. Human Molecular Genetics 163, 1163 (2023); https://doi.org/10.1093/hmg/ddad162.
Abstract	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.
Publisher	Oxford University Press (OUP)
Source Title	Human Molecular Genetics
Volume (Issue)	163
Page	1163
Date of Issued	2023-10-04
Language	English
Handle URL	https://hdl.handle.net/11094/93230
PISSN	09646906
eISSN	14602083
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1093/hmg/ddad162
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Human Molecular Genetics. 2023, 163, p. 1163
DC.title	Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension
DC.creator	Suginobe, Hidehiro
	Ishida, Hidekazu
	Ishii, Yoichiro
	Ueda, Kazutoshi
	Yoshihara, Chika
	Ueyama, Atsuko
	Wang, Renjie
	Tsuru, Hirofumi
	Hashimoto, Kazuhisa
	Hirose, Masaki
	Ishii, Ryo
	Narita, Jun
	Kitabatake, Yasuji
	Ozono, Keiichi
DC.publisher	Oxford University Press (OUP)
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2023-10-04
DC.identifier	https://doi.org/10.1093/hmg/ddad162
DC.subject	induced pluripotent stem cell
	Down syndrome ;endothelialcell
	endothelial cell
	EGR1
	pulmonaryhypertension
DC.description	Suginobe Hidehiro, Ishida Hidekazu, Ishii Yoichiro, et al. Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension. Human Molecular Genetics 163, 1163 (2023); https://doi.org/10.1093/hmg/ddad162.
DCTERMS.abstract	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.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
DC.format	93230
citation_title	Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension
citation_author	Suginobe, Hidehiro
	Ishida, Hidekazu
	Ishii, Yoichiro
	Ueda, Kazutoshi
	Yoshihara, Chika
	Ueyama, Atsuko
	Wang, Renjie
	Tsuru, Hirofumi
	Hashimoto, Kazuhisa
	Hirose, Masaki
	Ishii, Ryo
	Narita, Jun
	Kitabatake, Yasuji
	Ozono, Keiichi
citation_publisher	Oxford University Press (OUP)
citation_language	English
citation_date	2023-10-04
citation_journal_title	Human Molecular Genetics
citation_volume	163
citation_firstpage	1163
citation_doi	https://doi.org/10.1093/hmg/ddad162
citation_public_url	https://hdl.handle.net/11094/93230

Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension

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