Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response
Abstract Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving the vascular remodeling in PVOD. We show that the administration of MMC in rats mediates the activation of protein kinase R (PKR) and the integrated stress response (ISR), which lead to the release of the endothelial adhesion molecule VE-Cadherin in the complex with Rad51 to the circulation, disruption of endothelial barrier, and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates the depletion of VE-Cadherin, elevation of vascular permeability, and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygousBMPR2mutation that truncates the carboxyl tail of BMPR2, underscoring the role of deregulated BMP signal in the development of PVOD..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 29. Nov. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Prabhakar, Amit [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| doi: |
10.1101/2023.11.27.568924 |
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| PPN (Katalog-ID): |
XBI041684230 |
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| 245 | 1 | 0 | |a Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response |
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| 520 | |a Abstract Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving the vascular remodeling in PVOD. We show that the administration of MMC in rats mediates the activation of protein kinase R (PKR) and the integrated stress response (ISR), which lead to the release of the endothelial adhesion molecule VE-Cadherin in the complex with Rad51 to the circulation, disruption of endothelial barrier, and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates the depletion of VE-Cadherin, elevation of vascular permeability, and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygousBMPR2mutation that truncates the carboxyl tail of BMPR2, underscoring the role of deregulated BMP signal in the development of PVOD. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
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| 700 | 1 | |a Kumar, Rahul |4 aut | |
| 700 | 1 | |a Wadhwa, Meetu |4 aut | |
| 700 | 1 | |a Ghatpande, Prajakta |4 aut | |
| 700 | 1 | |a Zhang, Jingkun |4 aut | |
| 700 | 1 | |a Zhao, Ziwen |4 aut | |
| 700 | 1 | |a Lizama, Carlos O. |4 aut | |
| 700 | 1 | |a Kharbikar, Bhushan N. |0 (orcid)0000-0003-0394-0308 |4 aut | |
| 700 | 1 | |a Gräf, Stefan |0 (orcid)0000-0002-1315-8873 |4 aut | |
| 700 | 1 | |a Treacy, Carmen M. |4 aut | |
| 700 | 1 | |a Morrell, Nicholas W. |0 (orcid)0000-0001-5700-9792 |4 aut | |
| 700 | 1 | |a Graham, Brian B. |4 aut | |
| 700 | 1 | |a Lagna, Giorgio |4 aut | |
| 700 | 1 | |a Hata, Akiko |0 (orcid)0000-0003-3784-1738 |4 aut | |
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