GAS6 attenuates sepsis-induced cardiac dysfunction through NLRP3 inflammasome-dependent mechanism
Copyright © 2023 Elsevier Inc. All rights reserved..
Sepsis is a major health threat and often results in heart failure. Growth arrest-specific gene 6 (GAS6), a 75-kDa vitamin K-dependent protein, participates in immune regulation and inflammation through binding to AXL (the TAM receptor family). This study was designed to examine the myocardial regulatory role of GAS6 in sepsis. Serum GAS6 levels were increased in septic patients and mice while myocardial GAS6 levels were decreased in septic mice. Single-cell RNA sequencing further revealed a decline in GAS6 levels of nearly all cell clusters including cardiomyocytes. GAS6 overexpression via adeno-associated virus 9 (AAV9) overtly improved cardiac dysfunction in cecum ligation and puncture (CLP)-challenged mice, along with alleviated mitochondrial injury, endoplasmic reticulum stress, oxidative stress, and apoptosis. However, GAS6-elicited beneficial effects were removed by GAS6 knockout. The in vitro study was similar to these findings. Our data also noted a downstream effector role for NLRP3 in GAS6-initiated myocardial response. GAS6 knockout led to elevated levels of NLRP3, the effect of which was reconciled by GAS6 overexpression. Taken together, these results revealed the therapeutical potential of targeting GAS6/AXL-NLRP3 signaling in the management of heart anomalies in sepsis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:210 |
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| Enthalten in: |
Free radical biology & medicine - 210(2024) vom: 27. Jan., Seite 195-211 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ji, Ting [VerfasserIn] |
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| Links: |
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| Themen: |
CLP |
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| Anmerkungen: |
Date Completed 29.12.2023 Date Revised 17.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.freeradbiomed.2023.11.007 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364714239 |
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| 520 | |a Sepsis is a major health threat and often results in heart failure. Growth arrest-specific gene 6 (GAS6), a 75-kDa vitamin K-dependent protein, participates in immune regulation and inflammation through binding to AXL (the TAM receptor family). This study was designed to examine the myocardial regulatory role of GAS6 in sepsis. Serum GAS6 levels were increased in septic patients and mice while myocardial GAS6 levels were decreased in septic mice. Single-cell RNA sequencing further revealed a decline in GAS6 levels of nearly all cell clusters including cardiomyocytes. GAS6 overexpression via adeno-associated virus 9 (AAV9) overtly improved cardiac dysfunction in cecum ligation and puncture (CLP)-challenged mice, along with alleviated mitochondrial injury, endoplasmic reticulum stress, oxidative stress, and apoptosis. However, GAS6-elicited beneficial effects were removed by GAS6 knockout. The in vitro study was similar to these findings. Our data also noted a downstream effector role for NLRP3 in GAS6-initiated myocardial response. GAS6 knockout led to elevated levels of NLRP3, the effect of which was reconciled by GAS6 overexpression. Taken together, these results revealed the therapeutical potential of targeting GAS6/AXL-NLRP3 signaling in the management of heart anomalies in sepsis | ||
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| 700 | 1 | |a Yu, Liming |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Wangrui |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Chenxi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Junmin |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhenhua |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Zhenxing |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yang |e verfasserin |4 aut | |
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