Effects of FTMT Expression by Retinal Pigment Epithelial Cells on Features of Angiogenesis
Effects of FTMT Expression by Retinal Pigment Epithelial Cells on Features of Angiogenesis
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DOI：
10.3390/ijms21103635
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发表时间：
2020-05
影响因子：
5.6
通讯作者：
Undral Buyandelger;D. Walker;Daijiro Yanagisawa;T. Morimura;I. Tooyama
中科院分区：
文献类型：
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作者：
Undral Buyandelger;D. Walker;Daijiro Yanagisawa;T. Morimura;I. Tooyama
异常血管生成是许多疾病的病理特征，是血管生成因子对不同细胞应激反应的不协调表达所致。老年性黄斑变性(AMD)是导致视力丧失的主要原因，可由病理性血管生成引起。线粒体铁蛋白(FTMT)基因突变与AMD相关，探讨其在调节血管生成因子和血管生成中的可能作用。FTMT是一种铁隔离蛋白，主要在代谢活跃的细胞和高需氧量的组织中表达，包括视网膜。在这项研究中，我们利用人视网膜色素上皮细胞系ARPE-19作为未分化细胞和分化细胞。观察促炎症细胞因子、FTMT基因敲除、FTMT瞬时稳定过表达对促血管生成血管内皮细胞生长因子(VEGF)和抗血管生成色素上皮衍生因子(PEDF)表达的影响。促炎症细胞因子诱导FTMT和VEGFmRNA的表达，而抑制NF-κB显著降低FTMT的表达。在FTMT沉默的ARPE-19细胞中，VEGF蛋白和mRNA的表达显著增加。通过血管内皮细胞的体外血管生成实验，我们发现FTMT高表达细胞的条件培养液具有显著的抗血管生成作用。总之，我们的研究结果表明FTMT水平的升高可能通过降低血管内皮生长因子的水平和增加PEDF的表达来抑制血管生成。开发的细胞模型可以用来研究增加的FTMT是否对AMD等血管生成疾病具有保护作用。
Aberrant angiogenesis is a pathological feature of a number of diseases and arises from the uncoordinated expression of angiogenic factors as response to different cellular stresses. Age-related macular degeneration (AMD), a leading cause of vision loss, can result from pathological angiogenesis. As a mutation in the mitochondrial ferritin (FTMT) gene has been associated with AMD, its possible role in modulating angiogenic factors and angiogenesis was investigated. FTMT is an iron-sequestering protein primarily expressed in metabolically active cells and tissues with high oxygen demand, including retina. In this study, we utilized the human retinal pigment epithelial cell line ARPE-19, both as undifferentiated and differentiated cells. The effects of proinflammatory cytokines, FTMT knockdown, and transient and stable overexpression of FTMT were investigated on expression of pro-angiogenic vascular endothelial growth factor (VEGF) and anti-angiogenic pigment epithelial-derived factor (PEDF). Proinflammatory cytokines induced FTMT and VEGF expression, while NF-κB inhibition significantly reduced FTMT expression. VEGF protein and mRNA expression were significantly increased in FTMT-silenced ARPE-19 cells. Using an in vitro angiogenesis assay with endothelial cells, we showed that conditioned media from FTMT-overexpressing cells had significant antiangiogenic effects. Collectively, our findings indicate that increased levels of FTMT inhibit angiogenesis, possibly by reducing levels of VEGF and increasing PEDF expression. The cellular models developed can be used to investigate if increased FTMT may be protective in angiogenic diseases, such as AMD.