In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis
In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis
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DOI：
10.1073/pnas.0502287102
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发表时间：
2005-05-03
影响因子：
11.1
通讯作者：
Lindahl, U
中科院分区：
文献类型：
--
作者：
Li, JP;Galvis, MLE;Lindahl, U
淀粉样变性疾病包括20种内科疾病，包括淀粉样蛋白A(AA)淀粉样变性、阿尔茨海默病和2型糖尿病。这些情况的一个共同特征是选择性的器官沉积疾病特定的纤维蛋白，以及硫酸糖胺聚糖和硫酸乙酰肝素。我们已经培育出过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。在肝素酶过度产生的器官中，如肝脏和肾脏，观察到硫酸乙酰肝素链的急剧缩短。在实验诱导炎症相关性AA淀粉样变性时，这些部位选择性地逃脱淀粉样沉积，刚果红缺乏物质染色以及相关多糖的缺乏证实了这一点，而对照组动物的相同组织大量渗透淀粉样蛋白。相比之下，未能显著过度表达乙酰肝素酶的转基因小鼠的脾含有与对照小鼠相似的硫酸乙酰肝素链，并且仍然对淀粉样蛋白沉积敏感。我们的发现提供了直接的体内证据，证明硫酸乙酰肝素对淀粉样蛋白疾病的发展是必不可少的。
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.