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Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2023 Dec 12; Vol. 33 (1), pp. 78-90. - Publication Year :
- 2023
-
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.<br /> (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Humans
Cell Differentiation genetics
Endothelial Cells metabolism
PPAR gamma metabolism
Cells, Cultured
Early Growth Response Protein 1 genetics
Early Growth Response Protein 1 metabolism
Induced Pluripotent Stem Cells metabolism
Down Syndrome complications
Down Syndrome genetics
Down Syndrome metabolism
Hypertension, Pulmonary genetics
Pulmonary Arterial Hypertension metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 33
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 37792788
- Full Text :
- https://doi.org/10.1093/hmg/ddad162