Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension
© 2024 The Authors..
Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Acta pharmaceutica Sinica. B - 14(2024), 4 vom: 13. Apr., Seite 1726-1741 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xing, Yanjiang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 05.04.2024 published: Print-Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1016/j.apsb.2024.01.012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370615379 |
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| 100 | 1 | |a Xing, Yanjiang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension |
| 264 | 1 | |c 2024 | |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2024 The Authors. | ||
| 520 | |a Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Bone morphogenetic protein receptor II | |
| 650 | 4 | |a Endothelial-to-mesenchymal transition | |
| 650 | 4 | |a Lineage tracing | |
| 650 | 4 | |a Phosphodiesterase 4B | |
| 650 | 4 | |a Protein kinase A | |
| 650 | 4 | |a Pulmonary hypertension | |
| 650 | 4 | |a Side effects | |
| 650 | 4 | |a Vascular remodeling | |
| 700 | 1 | |a Hou, Yangfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Tianfei |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Ran |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Xiaohang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Bolun |e verfasserin |4 aut | |
| 700 | 1 | |a Pang, Junling |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Wenjun |e verfasserin |4 aut | |
| 700 | 1 | |a Shu, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Jinqiu |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Qilong |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Ya |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Xianmei |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Peiran |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Chaoyang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Hongmei |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Wenhui |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chen |e verfasserin |4 aut | |
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