Anti-recoverin antibodies induce an increase in intracellular calcium, leading to apoptosis in retinal cells
Anti-recoverin antibodies induce an increase in intracellular calcium, leading to apoptosis in retinal cells
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DOI：
10.1016/j.jaut.2005.11.007
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发表时间：
2006-03-01
影响因子：
12.8
通讯作者：
Duvoisin, RM
中科院分区：
文献类型：
--
作者：
Adamus, G;Webb, S;Duvoisin, RM
针对recoverin的自身抗体是一种在癌症相关性视网膜病变（CAR综合征）患者中发现的Ca 2+结合蛋白，其穿透视网膜细胞并通过线粒体途径诱导其凋亡。本研究的目的是研究抗recoverin抗体进入E1A.NR3视网膜细胞是否引起细胞内Ca 2+的变化。在用抗恢复蛋白抗体Rec-1、患者自身抗体以及对照大鼠和人IgG处理的活E1A.NR3视网膜细胞中，使用Ca 2+敏感性荧光染料Fura-2 AM测量细胞内Ca 2+。视网膜细胞在体外暴露于Rec-1抗体和CAR患者的自身抗体导致细胞内Ca 2+显著增加，而非特异性抗体不诱导这种效应。在L型钙通道阻断剂硝苯地平存在下，Rec-1与E1A.NR3细胞的共处理显著抑制了Ca 2+的增加。硝苯地平治疗还阻断了抗凋亡蛋白bcl-xL和促凋亡蛋白bax表达的变化。硝苯地平处理的细胞也表现出减少细胞溶质细胞色素c释放和减少半胱天冬酶3激活，相比，仅用Rec-1抗体处理的细胞。抗体诱导的Ca 2+的增加至少部分依赖于细胞外Ca 2+。硝苯地平被发现可以抑制Ca 2+进入细胞，并保护它们免受Rec-1诱导的凋亡。细胞内Ca 2+水平升高可能导致CAR综合征中的视网膜功能障碍和变性。我们的研究结果提供了一个分子基础，在CAR综合征的治疗中使用Ca 2+阻滞剂。(c)2005爱思唯尔有限公司保留所有权利。
Autoantibodies against recoverin, a Ca2+-binding protein found in patients with cancer-associated retinopathy (CAR syndrome), penetrate retinal cells and induce their apoptosis via a mitochondrial pathway. The goal of this study was to investigate whether the entry of anti-recoverin antibody into E1A.NR3 retinal cells causes a change in intracellular Ca2+. Intracellular Ca2+ was measured using the Ca2+-sensitive fluorescent dye Fura-2 AM in living E1A.NR3 retinal cells treated with anti-recoverin antibody Rec-1, patients' autoantibodies, and control rat and human IgG. The exposure of retinal cells to Rec-1 antibody and to the CAR patients' autoantibodies in vitro caused a significant increase in intracellular Ca2+, while non-specific antibodies did not induce such an effect. Co-treatment of the E1A.NR3 cells with Rec-1 in the presence of nifedipine, a L-type Ca2+ channel blocker, significantly suppressed the increase of Ca2+. Treatment with nifedipine also blocked changes in the antiapoptotic protein bcl-xL and in expressions of the pro-apoptotic protein bax. Nifedipine-treated cells also showed a decrease in cytosolic cytochrome c release and a decrease in caspase 3 activation, compared to cells treated only with Rec-1 antibody. The increase in the antibody-induced Ca2+ is at least in part dependent on extracellular Ca2+. Nifedipine was found to inhibit the entry of Ca2+ into the cells and to protect them from Rec-1-induced apoptosis. Increased levels of intracellular Ca2+ may lead to retinal dysfunction and degeneration in the CAR syndrome. Our results provide a molecular basis for the use of Ca2+ blockers in the treatment of the CAR syndrome. (c) 2005 Elsevier Ltd. All rights reserved.