P2Y2R activation by ATP induces oxLDL-mediated inflammasome activation through modulation of mitochondrial damage in human endothelial cells
Copyright © 2019. Published by Elsevier Inc..
Oxidative stress and the related inflammatory responses are closely associated with many diseases including cardiovascular diseases such as atherosclerosis. Especially, mitochondrial damage and inflammasome activation have been reported to be directly involved in atherogenesis. In addition, we previously reported that endothelial cells (ECs) exposed to oxidized LDL (oxLDL) release ATP, which activates P2Y2R, resulting in the expression of receptors for advanced glycation end products and adhesion molecules that are involved in the pathogenesis of atherosclerosis. Therefore, it is expected that P2Y2R activation by ATP released under inflammatory conditions may be linked to the inflammasome-mediated pathogenesis of cardiovascular diseases such as atherosclerosis. However, the exact association remains unclear. Thus, in this study, we investigated the role of P2Y2R in oxLDL-mediated inflammasome activation and the related atherosclerotic pathogenesis in ECs. ECs stimulated with oxLDL demonstrated increased intracellular production and extracellular secretion of ATP. In addition, mitochondrial reactive oxygen species (mtROS) production and mitochondrial DNA (mtDNA) expression and cytosolic release were increased in ECs stimulated with oxLDL or the P2Y2R agonists ATP and UTP. Moreover, caspase-1 activity and IL-1β production were increased in ECs stimulated with oxLDL, ATP or UTP through the modulation of mtROS production and mtDNA expression, in a P2Y2R-dependent manner. Furthermore, TLR-9 and NF-κB activation was increased in ECs in response to oxLDL, ATP or UTP, in a mtDNA-dependent manner. Taken together, our findings suggest that P2Y2R activation by ATP is involved in oxLDL-mediated inflammasome activation and subsequent IL-1β production through the modulation of mtROS-mtDNA induction and the TLR9-NF-κB signaling pathway.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:136 |
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| Enthalten in: |
Free radical biology & medicine - 136(2019) vom: 20. Mai, Seite 109-117 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jin, Hana [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 03.06.2020 Date Revised 03.06.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.freeradbiomed.2019.04.004 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM295806729 |
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| 245 | 1 | 0 | |a P2Y2R activation by ATP induces oxLDL-mediated inflammasome activation through modulation of mitochondrial damage in human endothelial cells |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019. Published by Elsevier Inc. | ||
| 520 | |a Oxidative stress and the related inflammatory responses are closely associated with many diseases including cardiovascular diseases such as atherosclerosis. Especially, mitochondrial damage and inflammasome activation have been reported to be directly involved in atherogenesis. In addition, we previously reported that endothelial cells (ECs) exposed to oxidized LDL (oxLDL) release ATP, which activates P2Y2R, resulting in the expression of receptors for advanced glycation end products and adhesion molecules that are involved in the pathogenesis of atherosclerosis. Therefore, it is expected that P2Y2R activation by ATP released under inflammatory conditions may be linked to the inflammasome-mediated pathogenesis of cardiovascular diseases such as atherosclerosis. However, the exact association remains unclear. Thus, in this study, we investigated the role of P2Y2R in oxLDL-mediated inflammasome activation and the related atherosclerotic pathogenesis in ECs. ECs stimulated with oxLDL demonstrated increased intracellular production and extracellular secretion of ATP. In addition, mitochondrial reactive oxygen species (mtROS) production and mitochondrial DNA (mtDNA) expression and cytosolic release were increased in ECs stimulated with oxLDL or the P2Y2R agonists ATP and UTP. Moreover, caspase-1 activity and IL-1β production were increased in ECs stimulated with oxLDL, ATP or UTP through the modulation of mtROS production and mtDNA expression, in a P2Y2R-dependent manner. Furthermore, TLR-9 and NF-κB activation was increased in ECs in response to oxLDL, ATP or UTP, in a mtDNA-dependent manner. Taken together, our findings suggest that P2Y2R activation by ATP is involved in oxLDL-mediated inflammasome activation and subsequent IL-1β production through the modulation of mtROS-mtDNA induction and the TLR9-NF-κB signaling pathway | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ATP | |
| 650 | 4 | |a Atherosclerosis | |
| 650 | 4 | |a IL-1β | |
| 650 | 4 | |a Inflammasome | |
| 650 | 4 | |a Oxidized LDL | |
| 650 | 4 | |a P2Y(2) receptor | |
| 650 | 4 | |a mtDNA | |
| 650 | 7 | |a Inflammasomes |2 NLM | |
| 650 | 7 | |a Lipoproteins, LDL |2 NLM | |
| 650 | 7 | |a Receptors, Purinergic P2Y2 |2 NLM | |
| 650 | 7 | |a oxidized low density lipoprotein |2 NLM | |
| 650 | 7 | |a Adenosine Triphosphate |2 NLM | |
| 650 | 7 | |a 8L70Q75FXE |2 NLM | |
| 700 | 1 | |a Ko, Young Shin |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Sang Won |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Hye Jung |e verfasserin |4 aut | |
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| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.freeradbiomed.2019.04.004 |3 Volltext |
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