Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type 1 causes cardiac fibrosis in mice
Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type 1 causes cardiac fibrosis in mice
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DOI：
10.1161/01.res.0000141427.61023.f4
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发表时间：
2004-09-17
影响因子：
20.1
通讯作者：
Dichek, DA
中科院分区：
文献类型：
--
作者：
Moriwaki, H;Stempien-Otero, A;Dichek, DA
一些研究暗示基质金属蛋白酶活性升高是心脏纤维化的一个原因。然而，尚不清楚其他蛋白酶是否也可以引发心脏纤维化。由于缺乏尿激酶型纤溶酶原激活物（uPA）可以防止小鼠实验性心肌梗死后心脏纤维化的发展，我们假设uPA活性升高或uPA抑制剂型纤溶酶原激活物抑制剂-1（派-1）缺乏可能导致心脏纤维化。我们使用具有清道夫受体（SR）导向的、巨噬细胞靶向的uPA过表达的小鼠（SR-uPA（+/0）小鼠）和派-1缺失小鼠来测试这些假设。我们的研究表明，SR-uPA（+/0）小鼠在5至10周龄之间开始发生心脏纤维化。纤维化之前是心脏巨噬细胞积聚，暗示uPA分泌巨噬细胞是纤维化发展的重要贡献者。分泌uPA的巨噬细胞在心脏纤维化发展中的关键作用得到了实验的支持，在这些实验中，来自SR-uPA（+/0）供体而不是非转基因供体的骨髓移植受体发生了心脏巨噬细胞积聚和纤维化。SR-uPA（+/0）小鼠和SR-uPA（+/0）骨髓受体在其他主要器官中既没有巨噬细胞积聚也没有纤维化，尽管这些器官中的uPA水平高于心脏。派-1基因敲除小鼠，而非同基因组，年龄匹配的对照组也在心脏中发生了巨噬细胞积聚和纤维化，但在其他器官中没有。我们得出结论：（1）升高的巨噬细胞uPA表达或派-1缺乏足以引起心脏巨噬细胞积聚和纤维化;（2）巨噬细胞是心脏纤维化发展的重要贡献者;和（3）心脏对过量uPA活性的作用特别敏感。
Several studies implicate elevated matrix metalloproteinase activity as a cause of cardiac fibrosis. However, it is unknown whether other proteases can also initiate cardiac fibrosis. Because absence of urokinase plasminogen activator (uPA) prevents development of cardiac fibrosis after experimental myocardial infarction in mice, we hypothesized that elevated activity of uPA or deficiency of the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) might cause cardiac fibrosis. We used mice with scavenger-receptor (SR)-directed, macrophage-targeted uPA overexpression (SR-uPA(+/0) mice) and PAI-1 null mice to test these hypotheses. Our studies revealed that SR-uPA(+/0) mice developed cardiac fibrosis beginning between 5 and 10 weeks of age. Fibrosis was preceded by cardiac macrophage accumulation, implicating uPA-secreting macrophages as important contributors to development of fibrosis. A key role for uPA-secreting macrophages in development of cardiac fibrosis was supported by experiments in which recipients of bone marrow transplants from SR-uPA(+/0) donors but not nontransgenic donors developed cardiac macrophage accumulation and fibrosis. SR-uPA(+/0) mice and recipients of SR-uPA(+/0) bone marrow had neither macrophage accumulation nor fibrosis in other major organs despite the presence of higher levels of uPA in these organs than in hearts. PAI-1 null mice but not congenic, age-matched controls also developed macrophage accumulation and fibrosis in hearts but not in other organs. We conclude: ( 1) either elevated macrophage uPA expression or PAI-1 deficiency is sufficient to cause cardiac macrophage accumulation and fibrosis; ( 2) macrophages are important contributors to the development of cardiac fibrosis; and ( 3) the heart is particularly sensitive to the effects of excess uPA activity.