α2 but Not α1 AMP-activated Protein Kinase Mediates Oxidative Stress-induced Inhibition of Retinal Pigment Epithelium Cell Phagocytosis of Photoreceptor Outer Segments*
α2 but Not α1 AMP-activated Protein Kinase Mediates Oxidative Stress-induced Inhibition of Retinal Pigment Epithelium Cell Phagocytosis of Photoreceptor Outer Segments*
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α2 但不是 α1 AMP 激活蛋白激酶介导氧化应激诱导的视网膜色素上皮细胞对感光器外节的吞噬作用的抑制*
DOI：
10.1074/jbc.m708848200
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发表时间：
2008
影响因子：
4.8
通讯作者：
G. D. De Vries
中科院分区：
文献类型：
--
作者：
S. Qin;G. D. De Vries
氧化应激导致视网膜色素上皮(RPE)细胞功能障碍，是导致干性老年性黄斑变性的主要危险因素。采用药理学和遗传学的方法，我们解决了亚致死性氧化应激抑制RPE细胞吞噬功能的机制。亚致死性氧化应激可剂量依赖性地抑制视网膜色素上皮细胞对光感受器外段的吞噬作用，激活的腺苷活化蛋白激酶α的Thr172和Ser79磷酸化水平及底物乙酰辅酶A羧基酶的活性分别增加。与氧化应激类似，AMPK的药理激活剂5-氨基咪唑-4-甲酰胺核苷(AICAR)以剂量依赖的方式抑制RPE细胞吞噬POS。AICAR对RPE细胞吞噬功能的抑制可被双嘧达莫阻断AICAR转位到细胞内，或被腺苷激酶抑制剂5-碘-结节苷抑制AICAR向ZMP的转化而完全逆转。同样地，AICAR诱导的AMPK激活可被双嘧达莫或5-碘杀菌素预先孵育所取消。基因敲除实验进一步证实，α-2而不是α-1AMPK参与了视网膜色素上皮细胞的吞噬功能，α-2AMPK的激活参与了氧化应激对细胞吞噬功能的抑制。α-2AMPK激活抑制RPE细胞吞噬功能与乙酰辅酶A羧化酶磷酸化显著增加有关。相比之下，AMPK在氧化应激诱导的RPE屏障功能破坏中没有作用。综上所述，氧化应激下POS负荷的减少可能会使RPE细胞处于自我保护状态。因此，激活AMPK对干性黄斑变性有治疗潜力。
Oxidative stress causes retinal pigment epithelium (RPE) cell dysfunction and is a major risk factor leading to the development of dry-type age-related macular degeneration. Taking pharmacological and genetic approaches, we address the mechanisms by which sublethal oxidative stress inhibits RPE cell phagocytosis. Sublethal oxidative stress dose-dependently inhibited RPE cell phagocytosis of photoreceptor outer segments (POS) and activated AMP-activated protein kinase (AMPK) as determined by increased Thr172 and Ser79 phosphorylation of AMPKα and its substrate acetyl-CoA carboxylase, respectively. Similar to oxidative stress, 5-aminoimidazole-4-carboxamide riboside (AICAR), a pharmacological activator of AMPK, inhibited RPE cell phagocytosis of POS in a dose-dependent manner. Inhibition of RPE cell phagocytosis by AICAR was fully reversed by blockade of AICAR translocation into cells by dipyridamole or inhibition of AICAR conversion to ZMP by adenosine kinase inhibitor 5-iodotubercidin. In agreement, AICAR-induced activation of AMPK was abolished by preincubation with dipyridamole or 5-iodotubercidin. Knock-out experiments further revealed that α2 but not α1 AMPK was involved in RPE cell phagocytosis and that activation of α2 AMPK contributed to the inhibition of RPE cell phagocytosis by oxidative stress. Inhibition of RPE cell phagocytosis by activation of α2 AMPK was associated with a dramatic increase in acetyl-CoA carboxylase phosphorylation. In comparison, AMPK had no role in oxidative stress-induced breakdown of RPE barrier function. Taken together, reduction in POS load under oxidative stress might direct RPE cells to a self-protected status. Thus, activating AMPK could have therapeutic potential in treating dry macular degeneration.
影响因子：
2.2
作者：
B. S. Winkler;M. Boulton;J. Gottsch;P. Sternberg
通讯作者：
B. S. Winkler;M. Boulton;J. Gottsch;P. Sternberg
影响因子：
4.4
作者：
David J. Tale;M. Miceli;David;-A.;Newsome
通讯作者：
David J. Tale;M. Miceli;David;-A.;Newsome
猪视网膜色素上皮在体外产生超氧化物。
影响因子：
4.4
作者：
Dorey,CK;Khouri,GG;Syniuta,LA;Curran,SA;Weiter,JJ
通讯作者：
Weiter,JJ