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Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage

Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal c...

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Autores principales: Notomi, Shoji, Hisatomi, Toshio, Murakami, Yusuke, Terasaki, Hiroto, Sonoda, Shozo, Asato, Ryo, Takeda, Atsunobu, Ikeda, Yasuhiro, Enaida, Hiroshi, Sakamoto, Taiji, Ishibashi, Tatsuro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540091/
https://www.ncbi.nlm.nih.gov/pubmed/23308196
http://dx.doi.org/10.1371/journal.pone.0053338
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author Notomi, Shoji
Hisatomi, Toshio
Murakami, Yusuke
Terasaki, Hiroto
Sonoda, Shozo
Asato, Ryo
Takeda, Atsunobu
Ikeda, Yasuhiro
Enaida, Hiroshi
Sakamoto, Taiji
Ishibashi, Tatsuro
author_facet Notomi, Shoji
Hisatomi, Toshio
Murakami, Yusuke
Terasaki, Hiroto
Sonoda, Shozo
Asato, Ryo
Takeda, Atsunobu
Ikeda, Yasuhiro
Enaida, Hiroshi
Sakamoto, Taiji
Ishibashi, Tatsuro
author_sort Notomi, Shoji
collection PubMed
description Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal circulation. However, the detailed mechanisms of this process remain elusive. Here we demonstrate that neovascular AMD with subretinal hemorrhage accompanies a significant increase in extracellular ATP, and that extracellular ATP initiates neurodegenerative processes through specific ligation of Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7; P2X7 receptor). Increased extracellular ATP levels were found in the vitreous samples of AMD patients with subretinal hemorrhage compared to control vitreous samples. Extravascular blood induced a massive release of ATP and photoreceptor cell apoptosis in co-culture with primary retinal cells. Photoreceptor cell apoptosis accompanied mitochondrial apoptotic pathways, namely activation of caspase-9 and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, as well as TUNEL-detectable DNA fragmentation. These hallmarks of photoreceptor cell apoptosis were prevented by brilliant blue G (BBG), a selective P2RX7 antagonist, which is an approved adjuvant in ocular surgery. Finally, in a mouse model of subretinal hemorrhage, photoreceptor cells degenerated through BBG-inhibitable apoptosis, suggesting that ligation of P2RX7 by extracellular ATP may accelerate photoreceptor cell apoptosis in AMD with subretinal hemorrhage. Our results indicate a novel mechanism that could involve neuronal cell death not only in AMD but also in hemorrhagic disorders in the CNS and encourage the potential application of BBG as a neuroprotective therapy.
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spelling pubmed-35400912013-01-10 Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage Notomi, Shoji Hisatomi, Toshio Murakami, Yusuke Terasaki, Hiroto Sonoda, Shozo Asato, Ryo Takeda, Atsunobu Ikeda, Yasuhiro Enaida, Hiroshi Sakamoto, Taiji Ishibashi, Tatsuro PLoS One Research Article Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal circulation. However, the detailed mechanisms of this process remain elusive. Here we demonstrate that neovascular AMD with subretinal hemorrhage accompanies a significant increase in extracellular ATP, and that extracellular ATP initiates neurodegenerative processes through specific ligation of Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7; P2X7 receptor). Increased extracellular ATP levels were found in the vitreous samples of AMD patients with subretinal hemorrhage compared to control vitreous samples. Extravascular blood induced a massive release of ATP and photoreceptor cell apoptosis in co-culture with primary retinal cells. Photoreceptor cell apoptosis accompanied mitochondrial apoptotic pathways, namely activation of caspase-9 and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, as well as TUNEL-detectable DNA fragmentation. These hallmarks of photoreceptor cell apoptosis were prevented by brilliant blue G (BBG), a selective P2RX7 antagonist, which is an approved adjuvant in ocular surgery. Finally, in a mouse model of subretinal hemorrhage, photoreceptor cells degenerated through BBG-inhibitable apoptosis, suggesting that ligation of P2RX7 by extracellular ATP may accelerate photoreceptor cell apoptosis in AMD with subretinal hemorrhage. Our results indicate a novel mechanism that could involve neuronal cell death not only in AMD but also in hemorrhagic disorders in the CNS and encourage the potential application of BBG as a neuroprotective therapy. Public Library of Science 2013-01-08 /pmc/articles/PMC3540091/ /pubmed/23308196 http://dx.doi.org/10.1371/journal.pone.0053338 Text en © 2013 Notomi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Notomi, Shoji
Hisatomi, Toshio
Murakami, Yusuke
Terasaki, Hiroto
Sonoda, Shozo
Asato, Ryo
Takeda, Atsunobu
Ikeda, Yasuhiro
Enaida, Hiroshi
Sakamoto, Taiji
Ishibashi, Tatsuro
Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage
title Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage
title_full Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage
title_fullStr Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage
title_full_unstemmed Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage
title_short Dynamic Increase in Extracellular ATP Accelerates Photoreceptor Cell Apoptosis via Ligation of P2RX7 in Subretinal Hemorrhage
title_sort dynamic increase in extracellular atp accelerates photoreceptor cell apoptosis via ligation of p2rx7 in subretinal hemorrhage
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540091/
https://www.ncbi.nlm.nih.gov/pubmed/23308196
http://dx.doi.org/10.1371/journal.pone.0053338
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