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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis
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In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis

机译：乙酰肝素酶过表达在体内使硫酸乙酰肝素断裂，使小鼠对淀粉样蛋白A淀粉样变性具有抗性

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摘要

Amyloid diseases encompass >20 medical disorders that include amyloid protein A (AA) amyloidosis, Alzheimer's disease, and type 2 diabetes. A common feature of these conditions is the selective organ deposition of disease-specific fibrillar proteins, along with the sulfated glycosaminoglycan, heparan sulfate. We have generated transgenic mice that overexpress human heparanase and have tested their susceptibility to amyloid induction. Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney. These sites selectively escaped amyloid deposition on experimental induction of inflammation-associated AA amyloidosis, as verified by lack of material staining with Congo Red, as well as lack of associated polysaccharide, whereas the same tissues from control animals were heavily infiltrated with amyloid. By contrast, the spleens of transgenic mice that failed to significantly overexpress heparanase contained heparan sulfate chains similar in size to those of control spleen and remained susceptible to amyloid deposition. Our findings provide direct in vivo evidence that heparan sulfate is essential for the development of amyloid disease.
机译：淀粉样变性疾病包括20多种医学疾病，包括淀粉样蛋白A（AA）淀粉样变性，阿尔茨海默氏病和2型糖尿病。这些病症的共同特征是疾病特异性原纤维蛋白以及硫酸化的糖胺聚糖硫酸乙酰肝素的选择性器官沉积。我们已经产生了过量表达人乙酰肝素酶的转基因小鼠，并测试了它们对淀粉样蛋白诱导的敏感性。在过量生产乙酰肝素的器官如肝和肾中观察到硫酸乙酰肝素链的急剧缩短。这些位点在实验性诱导炎症相关的AA淀粉样变性时选择性地逃避了淀粉样蛋白沉积，这通过缺乏刚果红的材料染色以及缺乏相关的多糖进行了验证，而来自对照动物的相同组织被淀粉样蛋白大量浸润。相比之下，未能明显过量表达乙酰肝素酶的转基因小鼠脾脏中含有硫酸乙酰肝素链，其大小与对照脾脏相似，并且仍易受淀粉样蛋白沉积的影响。我们的发现提供了直接的体内证据，表明硫酸乙酰肝素对于淀粉样变性病的发展至关重要。

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