Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation
Copyright © 2023. Published by Elsevier Ltd..
BACKGROUND: Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI.
METHODS: MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury.
RESULTS: Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury.
CONCLUSION: This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:183 |
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| Enthalten in: |
Journal of molecular and cellular cardiology - 183(2023) vom: 01. Okt., Seite 54-66 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xiao, Zilong [VerfasserIn] |
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| Links: |
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| Themen: |
Calpains |
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| Anmerkungen: |
Date Revised 11.10.2023 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.yjmcc.2023.08.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM361864957 |
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| 245 | 1 | 0 | |a Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status Publisher | ||
| 520 | |a Copyright © 2023. Published by Elsevier Ltd. | ||
| 520 | |a BACKGROUND: Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI | ||
| 520 | |a METHODS: MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury | ||
| 520 | |a RESULTS: Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury | ||
| 520 | |a CONCLUSION: This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Calpains | |
| 650 | 4 | |a Macrophages | |
| 650 | 4 | |a Mitochondria | |
| 650 | 4 | |a Myocardial infarction | |
| 650 | 4 | |a NLRP3 | |
| 700 | 1 | |a Wei, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Minghui |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ruizhen |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Yangang |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Ziqing |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Yixiu |e verfasserin |4 aut | |
| 700 | 1 | |a Ge, Junbo |e verfasserin |4 aut | |
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