Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved..
Mitophagy preserves microvascular structure and function during myocardial ischemia/reperfusion (I/R) injury. Empagliflozin, an anti-diabetes drug, may also protect mitochondria. We explored whether empagliflozin could reduce cardiac microvascular I/R injury by enhancing mitophagy. In mice, I/R injury induced luminal stenosis, microvessel wall damage, erythrocyte accumulation and perfusion defects in the myocardial microcirculation. Additionally, I/R triggered endothelial hyperpermeability and myocardial neutrophil infiltration, which upregulated adhesive factors and endothelin-1 but downregulated vascular endothelial cadherin and endothelial nitric oxide synthase in heart tissue. In vitro, I/R impaired the endothelial barrier function and integrity of cardiac microvascular endothelial cells (CMECs), while empagliflozin preserved CMEC homeostasis and thus maintained cardiac microvascular structure and function. I/R activated mitochondrial fission, oxidative stress and apoptotic signaling in CMECs, whereas empagliflozin normalized mitochondrial fission and fusion, neutralized supraphysiologic reactive oxygen species concentrations and suppressed mitochondrial apoptosis. Empagliflozin exerted these protective effects by activating FUNDC1-dependent mitophagy through the AMPKα1/ULK1 pathway. Both in vitro and in vivo, genetic ablation of AMPKα1 or FUNDC1 abolished the beneficial effects of empagliflozin on the myocardial microvasculature and CMECs. Taken together, the preservation of mitochondrial function through an activation of the AMPKα1/ULK1/FUNDC1/mitophagy pathway is the working mechanism of empagliflozin in attenuating cardiac microvascular I/R injury.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:52 |
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| Enthalten in: |
Redox biology - 52(2022) vom: 30. Juni, Seite 102288 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cai, Chen [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.05.2022 Date Revised 18.05.2023 published: Print-Electronic ErratumIn: Redox Biol. 2023 Jul;63:102738. - PMID 37202250 Citation Status MEDLINE |
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| doi: |
10.1016/j.redox.2022.102288 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM338560920 |
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| 245 | 1 | 0 | |a Empagliflozin attenuates cardiac microvascular ischemia/reperfusion through activating the AMPKα1/ULK1/FUNDC1/mitophagy pathway |
| 264 | 1 | |c 2022 | |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: Redox Biol. 2023 Jul;63:102738. - PMID 37202250 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a Mitophagy preserves microvascular structure and function during myocardial ischemia/reperfusion (I/R) injury. Empagliflozin, an anti-diabetes drug, may also protect mitochondria. We explored whether empagliflozin could reduce cardiac microvascular I/R injury by enhancing mitophagy. In mice, I/R injury induced luminal stenosis, microvessel wall damage, erythrocyte accumulation and perfusion defects in the myocardial microcirculation. Additionally, I/R triggered endothelial hyperpermeability and myocardial neutrophil infiltration, which upregulated adhesive factors and endothelin-1 but downregulated vascular endothelial cadherin and endothelial nitric oxide synthase in heart tissue. In vitro, I/R impaired the endothelial barrier function and integrity of cardiac microvascular endothelial cells (CMECs), while empagliflozin preserved CMEC homeostasis and thus maintained cardiac microvascular structure and function. I/R activated mitochondrial fission, oxidative stress and apoptotic signaling in CMECs, whereas empagliflozin normalized mitochondrial fission and fusion, neutralized supraphysiologic reactive oxygen species concentrations and suppressed mitochondrial apoptosis. Empagliflozin exerted these protective effects by activating FUNDC1-dependent mitophagy through the AMPKα1/ULK1 pathway. Both in vitro and in vivo, genetic ablation of AMPKα1 or FUNDC1 abolished the beneficial effects of empagliflozin on the myocardial microvasculature and CMECs. Taken together, the preservation of mitochondrial function through an activation of the AMPKα1/ULK1/FUNDC1/mitophagy pathway is the working mechanism of empagliflozin in attenuating cardiac microvascular I/R injury | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AMPKα1/ULK1 pathway | |
| 650 | 4 | |a Cardiac microvascular I/R injury | |
| 650 | 4 | |a Empagliflozin | |
| 650 | 4 | |a FUNDC1-Dependent mitophagy | |
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| 650 | 7 | |a FUNDC1 protein, mouse |2 NLM | |
| 650 | 7 | |a Glucosides |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Mitochondrial Proteins |2 NLM | |
| 650 | 7 | |a empagliflozin |2 NLM | |
| 650 | 7 | |a HDC1R2M35U |2 NLM | |
| 700 | 1 | |a Guo, Zhongzhou |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Xing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ziying |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a He, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Tiantian |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Kangrong |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Nengxian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Toan, Sam |e verfasserin |4 aut | |
| 700 | 1 | |a Muid, David |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Ying |e verfasserin |4 aut | |
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