Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice
Modification of apolipoprotein(a) lysine binding site reduces atherosclerosis in transgenic mice
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DOI：
10.1172/jci119565
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发表时间：
1997-08-01
影响因子：
15.9
通讯作者：
Lawn, RM
中科院分区：
文献类型：
--
作者：
Boonmark, NW;Lou, XJ;Lawn, RM
脂蛋白（a）通过其纤溶酶原样载脂蛋白（a）组分与纤维蛋白和其他纤溶酶原底物结合而促进动脉粥样硬化的发展。载脂蛋白（a）在其kringle结构域之一中含有主要的赖氨酸结合位点，通过诱变破坏该位点大大降低了载脂蛋白（a）与赖氨酸和纤维蛋白的结合，在近交系小鼠品系中已经产生了表达载脂蛋白（a）的这种突变形式的转基因小鼠以及表达野生型载脂蛋白（a）的小鼠，与赖氨酸结合位点突变株和非转基因同窝小鼠相比，野生型载脂蛋白（a）转基因小鼠脂质病变的发生增加了5倍，主动脉中载脂蛋白（a）的局灶性沉积也大幅增加。结果表明，在小鼠模型系统中，该赖氨酸结合位点在载脂蛋白（a）的致病活性中起关键作用。
Lipoprotein(a) contributes to the development of atherosclerosis through the binding of its plasminogen-like apolipoprotein(a) component to fibrin and other plasminogen substrates. Apolipoprotein(a) contains a major lysine binding site in one of its kringle domains, Destruction of this site by mutagenesis greatly reduces the binding of apolipoprotein(a) to lysine and fibrin, Transgenic mice expressing this mutant form of apolipoprotein(a) as well as mice expressing wild-type apolipoprotein(a) have been created in an inbred mouse strain, The wild-type apolipoprotein(a) transgenic mice have a fivefold increase in the development of lipid lesions, as well as a large increase in the focal deposition of apolipoprotein(a) in the aorta, compared with the lysine binding site mutant strain and to nontransgenic littermates. The results demonstrate the key role of this lysine binding site in the pathogenic activity of apolipoprotein(a) in a murine model system.