Dynamic increase in extracellular ATP accelerates photoreceptor cell apoptosis via ligation of P2RX7 in subretinal hemorrhage.
Dynamic increase in extracellular ATP accelerates photoreceptor cell apoptosis via ligation of P2RX7 in subretinal hemorrhage.
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DOI：
10.1371/journal.pone.0053338
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ishibashi T
中科院分区：
文献类型：
--
作者：
Notomi S;Hisatomi T;Murakami Y;Terasaki H;Sonoda S;Asato R;Takeda A;Ikeda Y;Enaida H;Sakamoto T;Ishibashi T
光感受器变性是年龄相关性黄斑变性（AMD）中视力损害的最重要原因。在新血管型AMD中，由于脉络膜新生血管（CNV），脉络膜循环中异常血管的生长，视网膜下出血导致严重的光感受器丧失。然而，这一过程的详细机制仍然难以捉摸。本研究表明，伴有视网膜下出血的新生血管性AMD伴随着细胞外ATP的显著增加，细胞外ATP通过嘌呤能受体P2X、配体门控离子通道7 （P2RX7； P2X7受体）的特异性连接启动神经退行性过程。与对照玻璃体样本相比，视网膜下出血的AMD患者玻璃体样本中发现细胞外ATP水平升高。与原代视网膜细胞共培养时，血管外血液诱导ATP大量释放和光感受器细胞凋亡。光感受器细胞凋亡伴随着线粒体凋亡途径，即caspase-9的激活和凋亡诱导因子（AIF）从线粒体向细胞核的易位，以及tunel可检测的DNA片段。亮蓝G （BBG）是一种选择性P2RX7拮抗剂，是一种被批准用于眼部手术的佐剂，它可以阻止这些感光细胞凋亡的标志。最后，在视网膜下出血小鼠模型中，光感受器细胞通过bbg抑制的凋亡变性，提示细胞外ATP结扎P2RX7可能加速AMD合并视网膜下出血的光感受器细胞凋亡。我们的研究结果提示了一种新的机制，不仅涉及AMD的神经元细胞死亡，还涉及中枢神经系统出血性疾病，并鼓励BBG作为神经保护治疗的潜在应用。
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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影响因子：
--
作者：
Hisatomi, T;Enaida, H;Ishibashi, T
通讯作者：
Ishibashi, T
影响因子：
2.3
作者：
Jimena Ricatti, Maria;Alfie, Lionel D.;Paula Faillace, Maria
通讯作者：
Paula Faillace, Maria
影响因子：
3.5
作者：
Ferrari, D;Los, M;Schulze-Osthoff, K
通讯作者：
Schulze-Osthoff, K
影响因子：
4.2
作者：
GLATT, H;MACHEMER, R
通讯作者：
MACHEMER, R
影响因子：
64.5
作者：
ELLIS, HM;HORVITZ, HR
通讯作者：
HORVITZ, HR