Alpha-melanocyte stimulating hormone protects retinal pigment epithelium cells from oxidative stress through activation of melanocortin 1 receptor-Akt-mTOR signaling
Alpha-melanocyte stimulating hormone protects retinal pigment epithelium cells from oxidative stress through activation of melanocortin 1 receptor-Akt-mTOR signaling
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DOI：
10.1016/j.bbrc.2013.11.113
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发表时间：
2014-01-10
影响因子：
3.1
通讯作者：
Jiang, Qin
中科院分区：
文献类型：
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作者：
Cheng, Li-bo;Cheng, Lei;Jiang, Qin
老年性黄斑变性(AMD)患者会出现视野中央的视力丧失。活性氧(ROS)介导的视网膜色素上皮(RPE)细胞凋亡是AMD发病的重要因素。在这项研究中，我们探讨了α-黑素细胞刺激素(α-MSH)对氧化应激RPE细胞的促存活作用。我们发现α-MSH受体黑素皮质素I受体(MC1R)在原代和转化的RPE细胞中有功能性表达。RPE细胞对α-MSH刺激有反应。α-MSH可激活RPE细胞中Akt/哺乳动物雷帕霉素靶点(MTOR)和ERK1/2信号，而MC1R siRNA抑制该信号通路。α-MSH保护RPE细胞免受过氧化氢(H_2O_2)诱导的凋亡，当MC1R被siRNA耗尽时，这种作用几乎被消除。Akt抑制剂(Perifosine、MK-2206和LY294002)可抑制α-MSH介导的S6K1活化和对H_2O_2的促存活作用。此外，用雷帕霉素或mTOR siRNA敲除mTOR可减弱α-MSH在RPE细胞中的促存活作用。因此，Akt及其下游的mTOR信号介导了α-MSH诱导的RPE细胞的存活。综上所述，我们已经确定了一条新的α-MSH-MC1R生理通路，它可以减少H_2O_2诱导的RPE细胞损伤，并可能将发生AMD的风险降至最低。(C)2013 Elsevier Inc.保留所有权利。
Patients with age related macular degeneration (AMD) will develop vision loss in the center of the visual field. Reactive oxygen species (ROS)-mediated retinal pigment epithelium (RPE) cell apoptosis is an important contributor of AMD. In this study, we explored the pro-survival effect of alpha-melanocyte stimulating hormone (alpha-MSH) on oxidative stressed RPE cells. We found that alpha-MSH receptor melanocortin I receptor (MC1R) was functionally expressed in primary and transformed RPE cells. RPE cells were response to alpha-MSH stimulation. alpha-MSH activated Akt/mammalian target of rapamycin (mTOR) and Erk1/2 signalings in RPE cells, which were inhibited by MC1R siRNA knockdown. alpha-MSH protected RPE cells from hydrogen peroxide (H2O2)-induced apoptosis, an effect that was almost abolished when MC1R was depleted by siRNA. alpha-MSH-mediated S6K1 activation and pro-survival effect against H2O2 was inhibited by Akt inhibitors (perifosine, MK-2206 and LY294002). Further, mTOR inhibition by rapamycin, or by mTOR siRNA knockdown, diminished alpha-MSH's pro-survival effect in RPE cells. Thus, Akt and its downstream mTOR signaling mediates alpha-MSH-induced survival in RPE cells. In summary, we have identified a new alpha-MSH-MC1R physiologic pathway that reduces H2O2-induced RPE cell damage, and might minimize the risk of developing AMD. (C) 2013 Elsevier Inc. All rights reserved.