Mitomycin C induces pulmonary vascular endothelial-to-mesenchymal transition and pulmonary veno-occlusive disease via Smad3-dependent pathway in rats
© 2020 The British Pharmacological Society..
BACKGROUND AND PURPOSE: Pulmonary veno-occlusive disease (PVOD) is a rare disease characterized by the obstruction of small pulmonary veins leading to pulmonary hypertension. However, the mechanisms underlying pulmonary vessel occlusion remain largely unclear.
EXPERIMENTAL APPROACH: A mitomycin C (MMC)-induced PVOD rat model was used as in vivo animal model, and primarily cultured rat pulmonary microvascular endothelial cells (PMVECs) were used as in vitro cell model.
KEY RESULTS: Our data suggested an endothelial-to-mesenchymal transition (EndoMT) may be present in the pulmonary microvessels isolated from either PVOD patients or MMC-induced PVOD rats. In comparison to the control vessels, vessels from both PVOD patients and PVOD rats had co-localized staining of specific endothelial marker von Willebrand factor (vWF) and mesenchymal marker α-smooth muscle actin (α-SMA), suggesting the presence of cells that co-express endothelial and mesenchymal markers. In both the lung tissues of MMC-induced PVOD rats and MMC-treated rat PMVECs there were decreased levels of endothelial markers (e.g. VE-cadherin and CD31) and increased mesenchymal markers (e.g. vimentin, fibronectin and α-SMA) were detected indicating EndoMT. Moreover, MMC-induced activation of the TGFβ/Smad3/Snail axis, while blocking this pathway with either selective Smad3 inhibitor (SIS3) or small interfering RNA (siRNA) against Smad3, dramatically abolished the MMC-induced EndoMT. Notably, treatment with SIS3 remarkably prevented the pathogenesis of MMC-induced PVOD in rats.
CONCLUSIONS AND IMPLICATIONS: Our data indicated that targeted inhibition of Smad3 leads to a potential, novel strategy for PVOD therapy, likely by inhibiting the EndoMT in pulmonary microvasculature.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:178 |
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| Enthalten in: |
British journal of pharmacology - 178(2021), 1 vom: 03. Jan., Seite 217-235 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Chenting [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.06.2021 Date Revised 21.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bph.15314 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM317091328 |
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| 100 | 1 | |a Zhang, Chenting |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mitomycin C induces pulmonary vascular endothelial-to-mesenchymal transition and pulmonary veno-occlusive disease via Smad3-dependent pathway in rats |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 21.06.2021 | ||
| 500 | |a Date Revised 21.06.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 The British Pharmacological Society. | ||
| 520 | |a BACKGROUND AND PURPOSE: Pulmonary veno-occlusive disease (PVOD) is a rare disease characterized by the obstruction of small pulmonary veins leading to pulmonary hypertension. However, the mechanisms underlying pulmonary vessel occlusion remain largely unclear | ||
| 520 | |a EXPERIMENTAL APPROACH: A mitomycin C (MMC)-induced PVOD rat model was used as in vivo animal model, and primarily cultured rat pulmonary microvascular endothelial cells (PMVECs) were used as in vitro cell model | ||
| 520 | |a KEY RESULTS: Our data suggested an endothelial-to-mesenchymal transition (EndoMT) may be present in the pulmonary microvessels isolated from either PVOD patients or MMC-induced PVOD rats. In comparison to the control vessels, vessels from both PVOD patients and PVOD rats had co-localized staining of specific endothelial marker von Willebrand factor (vWF) and mesenchymal marker α-smooth muscle actin (α-SMA), suggesting the presence of cells that co-express endothelial and mesenchymal markers. In both the lung tissues of MMC-induced PVOD rats and MMC-treated rat PMVECs there were decreased levels of endothelial markers (e.g. VE-cadherin and CD31) and increased mesenchymal markers (e.g. vimentin, fibronectin and α-SMA) were detected indicating EndoMT. Moreover, MMC-induced activation of the TGFβ/Smad3/Snail axis, while blocking this pathway with either selective Smad3 inhibitor (SIS3) or small interfering RNA (siRNA) against Smad3, dramatically abolished the MMC-induced EndoMT. Notably, treatment with SIS3 remarkably prevented the pathogenesis of MMC-induced PVOD in rats | ||
| 520 | |a CONCLUSIONS AND IMPLICATIONS: Our data indicated that targeted inhibition of Smad3 leads to a potential, novel strategy for PVOD therapy, likely by inhibiting the EndoMT in pulmonary microvasculature | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Smad3 | |
| 650 | 4 | |a endothelial-to-mesenchymal transition | |
| 650 | 4 | |a mitomycin C | |
| 650 | 4 | |a pulmonary microvascular endothelial cell | |
| 650 | 4 | |a pulmonary veno-occlusive disease | |
| 650 | 7 | |a SMAD3 protein, human |2 NLM | |
| 650 | 7 | |a Smad3 Protein |2 NLM | |
| 650 | 7 | |a Mitomycin |2 NLM | |
| 650 | 7 | |a 50SG953SK6 |2 NLM | |
| 700 | 1 | |a Lu, Wenju |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Xiaoyun |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Shiyun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Qiuyu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wenyan |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Xuefen |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuqin |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zizhou |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Guoping |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jiyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Haixia |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Chunli |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Haiyang |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Dejun |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jian |e verfasserin |4 aut | |
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