Overexpression of HTRA1 leads to ultrastructural changes in the elastic layer of Bruch's membrane via cleavage of extracellular matrix components.
Overexpression of HTRA1 leads to ultrastructural changes in the elastic layer of Bruch's membrane via cleavage of extracellular matrix components.
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DOI：
10.1371/journal.pone.0022959
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Fauser S
中科院分区：
文献类型：
--
作者：
Vierkotten S;Muether PS;Fauser S
染色体区域10 q26的变异与年龄相关性黄斑变性（AMD）的风险增加密切相关。两个潜在的AMD基因位于该区域：ARMS 2和HTRA 1（高温要求A1）。以往的研究表明，HTRA 1启动子区的多态性导致HTRA 1蛋白的过表达。本研究旨在探讨HTRA 1过表达在AMD发病机制中的作用。产生在视网膜色素上皮（RPE）层中过表达鼠蛋白的转基因Htra 1小鼠，并通过透射电子显微镜、免疫荧光染色和Western印迹分析来表征。在Htra 1转基因小鼠中的布鲁赫膜（BM）的弹性层是片段化的，并且比野生型（WT）对照中的连续性更低。缺乏N-末端结构域的重组HTRA 1切割各种细胞外基质（ECM）蛋白。随后的蛋白质印迹分析显示，与WT相比，转基因小鼠的RPE/脉络膜层中纤连蛋白片段的过表达和纤蛋白5和弹性蛋白原的减少。Fibulin 5通过促进弹性纤维的组装和成熟而对弹性发生至关重要。综上所述，我们的数据表明HTRA 1过表达通过fibulin 5切割导致BM弹性发生改变。它强调了ECM相关蛋白在AMD发展中的重要性，并将HTRA 1与其他AMD风险基因如fibulin 5，fibulin 6，ARMS 2和TIMP 3联系起来。
Variants in the chromosomal region 10q26 are strongly associated with an increased risk for age-related macular degeneration (AMD). Two potential AMD genes are located in this region: ARMS2 and HTRA1 (high-temperature requirement A1). Previous studies have suggested that polymorphisms in the promotor region of HTRA1 result in overexpression of HTRA1 protein. This study investigated the role of HTRA1 overexpression in the pathogenesis of AMD. Transgenic Htra1 mice overexpressing the murine protein in the retinal pigment epithelium (RPE) layer of the retina were generated and characterized by transmission electron microscopy, immunofluorescence staining and Western Blot analysis. The elastic layer of Bruch's membrane (BM) in the Htra1 transgenic mice was fragmented and less continuous than in wild type (WT) controls. Recombinant HTRA1 lacking the N-terminal domain cleaved various extracellular matrix (ECM) proteins. Subsequent Western Blot analysis revealed an overexpression of fibronectin fragments and a reduction of fibulin 5 and tropoelastin in the RPE/choroid layer in transgenic mice compared to WT. Fibulin 5 is essential for elastogenesis by promoting elastic fiber assembly and maturation. Taken together, our data implicate that HTRA1 overexpression leads to an altered elastogenesis in BM through fibulin 5 cleavage. It highlights the importance of ECM related proteins in the development of AMD and links HTRA1 to other AMD risk genes such as fibulin 5, fibulin 6, ARMS2 and TIMP3.
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