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

アクセス数:1,570件（2025-07-22 20:52 集計）

固定URL: https://hdl.handle.net/11094/93230

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タイトル	Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension
著者	著者名 Suginobe, Hidehiro
	NRID 1000050467552 1000050467552 researchmap permalink researcher_cardio researcher_cardio Scopus Author ID 36863872000 36863872000 著者名 Ishida, Hidekazu
	NRID 1000090573882 1000090573882 著者名 Ishii, Yoichiro
	著者名 Ueda, Kazutoshi
	著者名 Yoshihara, Chika
	著者名 Ueyama, Atsuko
	著者名 Wang, Renjie
	著者名 Tsuru, Hirofumi
	著者名 Hashimoto, Kazuhisa
	researchmap permalink masahirose masahirose Scopus Author ID 57908743200 57908743200 NRID 1000010973662 1000010973662 著者名 Hirose, Masaki
	NRID 1000090794008 1000090794008 researchmap permalink iryo-0918 iryo-0918 Scopus Author ID 56017974100 56017974100 著者名 Ishii, Ryo
	NRID 1000070467562 1000070467562 researchmap permalink J-narita J-narita Scopus Author ID 36993204400 36993204400 著者名 Narita, Jun
	NRID 1000080506494 1000080506494 ORCID 0000-0002-2907-9512 0000-0002-2907-9512 researchmap permalink kyasuji kyasuji Scopus Author ID 7003894272 7003894272 著者名 Kitabatake, Yasuji
	NRID 1000020270770 1000020270770 researchmap permalink read0092357 read0092357 Scopus Author ID 55545335700 55545335700 著者名 Ozono, Keiichi
キーワード等	induced pluripotent stem cell
	Down syndrome ;endothelialcell
	endothelial cell
	EGR1
	pulmonaryhypertension
内容	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.
抄録	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.
出版者	Oxford University Press (OUP)
収録物名	Human Molecular Genetics
巻(号)	163
ページ	1163
刊行年月	2023-10-04
言語	英語
ハンドルURL	https://hdl.handle.net/11094/93230
PISSN	09646906
eISSN	14602083
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1093/hmg/ddad162
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCMI資源タイプ	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	英語
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	英語
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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