Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation
Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation
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DOI：
10.1111/j.1538-7836.2008.03183.x
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发表时间：
2008-12-01
影响因子：
10.4
通讯作者：
Koschinsky, M. L.
中科院分区：
文献类型：
--
作者：
Feric, N. T.;Boffa, M. B.;Koschinsky, M. L.
背景：血浆脂蛋白（a）[Lp（a）]浓度升高与血栓性疾病风险增加相关。脂蛋白（a）是一种独特的脂蛋白，由低密度脂蛋白样部分共价连接到载脂蛋白（a）[apo（a）]（纤溶酶原纤溶酶原的同系物）。几项体外和体内研究表明，Lp（a）/apo（a）可抑制纤维蛋白表面组织型纤溶酶原激活剂介导的纤溶酶原激活，尽管apo（a）的抑制机制仍存在争议。对于纤维蛋白凝块溶解至关重要的是许多纤溶酶依赖性正反馈反应，其增强纤溶酶原活化的效率，包括纤溶酶介导的Glu-纤溶酶原向Lys-纤溶酶原的转化。目的：使用酸-尿素凝胶电泳分离两种形式的放射性标记纤溶酶原，我们确定apo（a）是否能够抑制Glu-纤溶酶原转化为Lys-纤溶酶原。研究方法：在不存在或存在不同重组载脂蛋白（a）物质的情况下进行试验，包括点突变体、缺失突变体和代表90%以上已知载脂蛋白（a）亚型大小的变体。结果：Apo（a）显著抑制Glu-纤溶酶原的转化。确定了Kringle IV 5-9型和Kringle V的关键作用;还观察到分子氨基末端一半内序列的贡献作用。此外，除了apo（a）的最小天然亚型外，发现亚型大小对apo（a）的抑制能力没有贡献。结论：这些发现强调了对了解Lp（a）/apo（a）介导的纤溶酶原激活抑制的新贡献：Lp（a）的apo（a）组分抑制纤溶酶介导的Glu-纤溶酶原转化为Lys-纤溶酶原的关键正反馈步骤的能力。
Background: Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are associated with an increased risk for thrombotic disorders. Lp(a) is a unique lipoprotein consisting of a low-density lipoprotein-like moiety covalently linked to apolipoprotein(a) [apo(a)], a homologue of the fibrinolytic proenzyme plasminogen. Several in vitro and in vivo studies have shown that Lp(a)/apo(a) can inhibit tissue-type plasminogen activator-mediated plasminogen activation on fibrin surfaces, although the mechanism of inhibition by apo(a) remains controversial. Essential to fibrin clot lysis are a number of plasmin-dependent positive feedback reactions that enhance the efficiency of plasminogen activation, including the plasmin-mediated conversion of Glu-plasminogen to Lys-plasminogen. Objective: Using acid-urea gel electrophoresis to resolve the two forms of radiolabeled plasminogen, we determined whether apo(a) is able to inhibit Glu-plasminogen to Lys-plasminogen conversion. Methods: The assays were performed in the absence or presence of different recombinant apo(a) species, including point mutants, deletion mutants and variants that represent greater than 90% of the known apo(a) isoform sizes. Results: Apo(a) substantially suppressed Glu-plasminogen conversion. Critical roles were identified for the kringle IV types 5-9 and kringle V; contributory roles for sequences within the amino-terminal half of the molecule were also observed. Additionally, with the exception of the smallest naturally-occurring isoform of apo(a), isoform size was found not to contribute to the inhibitory capacity of apo(a). Conclusion: These findings underscore a novel contribution to the understanding of Lp(a)/apo(a)-mediated inhibition of plasminogen activation: the ability of the apo(a) component of Lp(a) to inhibit the key positive feedback step of plasmin-mediated Glu-plasminogen to Lys-plasminogen conversion.