Downregulation of PDCD4 through STAT3/ATF6/autophagy mediates MIF-induced PASMCs proliferation/migration and vascular remodeling
Copyright © 2023 Elsevier B.V. All rights reserved..
To address the molecular mechanisms underlying macrophage migration inhibitory factor (MIF) induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration and vascular remodeling in pulmonary hypertension (PH), primary cultured rat PASMCs and monocrotaline (MCT)-induced rats with PH were applied in the present study. The results showed that MIF increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, and then stimulated activating transcription factor 6 (ATF6) activation, subsequently triggered autophagy activation, which further led to programmed cell death factor 4 (PDCD4) lysosomal degradation, and eventually promoted PASMCs proliferation/migration. In lung tissues of MCT rats, MIF protein expression was elevated, phosphorylation of STAT3 and activation of ATF6 were increased, activation of autophagy was evident, and reduction of PDCD4 was observed. Intervention with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP), ATF6 blocker melatonin or autophagy inhibitor chloroquine, confirmed the in vitro interaction among MIF, STAT3, ATF6, autophagy and PDCD4 in MCT induced rats with PH. Targeting MIF/STAT3/ATF6/autophagy/PDCD4 axis effectively prevented the development of PH by suppressing PASMCs proliferation and vascular remodeling. In conclusions, we demonstrate that MIF activates the STAT3/ATF6/autophagy cascade and then degrades PDCD4 leading to PASMCs proliferation/migration and pulmonary vascular remodeling, suggesting that intervention this axis might have potential value in management of PH.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:956 |
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| Enthalten in: |
European journal of pharmacology - 956(2023) vom: 05. Okt., Seite 175968 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chai, Limin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.09.2023 Date Revised 21.09.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejphar.2023.175968 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM36049384X |
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| 100 | 1 | |a Chai, Limin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Downregulation of PDCD4 through STAT3/ATF6/autophagy mediates MIF-induced PASMCs proliferation/migration and vascular remodeling |
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| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a To address the molecular mechanisms underlying macrophage migration inhibitory factor (MIF) induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration and vascular remodeling in pulmonary hypertension (PH), primary cultured rat PASMCs and monocrotaline (MCT)-induced rats with PH were applied in the present study. The results showed that MIF increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, and then stimulated activating transcription factor 6 (ATF6) activation, subsequently triggered autophagy activation, which further led to programmed cell death factor 4 (PDCD4) lysosomal degradation, and eventually promoted PASMCs proliferation/migration. In lung tissues of MCT rats, MIF protein expression was elevated, phosphorylation of STAT3 and activation of ATF6 were increased, activation of autophagy was evident, and reduction of PDCD4 was observed. Intervention with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP), ATF6 blocker melatonin or autophagy inhibitor chloroquine, confirmed the in vitro interaction among MIF, STAT3, ATF6, autophagy and PDCD4 in MCT induced rats with PH. Targeting MIF/STAT3/ATF6/autophagy/PDCD4 axis effectively prevented the development of PH by suppressing PASMCs proliferation and vascular remodeling. In conclusions, we demonstrate that MIF activates the STAT3/ATF6/autophagy cascade and then degrades PDCD4 leading to PASMCs proliferation/migration and pulmonary vascular remodeling, suggesting that intervention this axis might have potential value in management of PH | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ATF6 | |
| 650 | 4 | |a Autophagy | |
| 650 | 4 | |a MIF | |
| 650 | 4 | |a PDCD4 | |
| 650 | 4 | |a Pulmonary hypertension | |
| 650 | 7 | |a Activating Transcription Factor 6 |2 NLM | |
| 650 | 7 | |a Macrophage Migration-Inhibitory Factors |2 NLM | |
| 650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
| 650 | 7 | |a Pdcd4 protein, rat |2 NLM | |
| 650 | 7 | |a Apoptosis Regulatory Proteins |2 NLM | |
| 700 | 1 | |a Wang, Qingting |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Danyang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qianqian |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuqian |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Huan |e verfasserin |4 aut | |
| 700 | 1 | |a Qiu, Yuanjie |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Nirui |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Xinming |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Manxiang |e verfasserin |4 aut | |
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