Inhibition of DYRK1A attenuates vascular remodeling in pulmonary arterial hypertension via suppressing STAT3/Pim-1/NFAT pathway
Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro. Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 2023 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:46 |
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| Enthalten in: |
Clinical and experimental hypertension (New York, N.Y. : 1993) - 46(2023), 1 vom: 31. Dez., Seite 2297642 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lan, Cong [VerfasserIn] |
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| Links: |
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| Themen: |
4FHH5G48T7 |
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| Anmerkungen: |
Date Completed 28.12.2023 Date Revised 28.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1080/10641963.2023.2297642 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366380966 |
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| 245 | 1 | 0 | |a Inhibition of DYRK1A attenuates vascular remodeling in pulmonary arterial hypertension via suppressing STAT3/Pim-1/NFAT pathway |
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| 520 | |a Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro. Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DYRK1A | |
| 650 | 4 | |a PASMCs | |
| 650 | 4 | |a STAT3/Pim-1/NFAT pathway | |
| 650 | 4 | |a pulmonary arterial hypertension | |
| 650 | 4 | |a vascular remodeling | |
| 650 | 7 | |a Harmine |2 NLM | |
| 650 | 7 | |a 4FHH5G48T7 |2 NLM | |
| 650 | 7 | |a STAT3 protein, human |2 NLM | |
| 650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
| 700 | 1 | |a Fang, Guangyao |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Chenming |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiuchuan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Fengyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yongjian |e verfasserin |4 aut | |
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