巨噬细胞靶向性过表达尿激酶会导致动脉粥样硬化加速、冠状动脉闭塞和过早死亡。
Macrophage-targeted overexpression of urokinase causes accelerated atherosclerosis, coronary artery occlusions, and premature death.
作者信息
Cozen Aaron E, Moriwaki Hideaki, Kremen Michal, DeYoung Mary Beth, Dichek Helén L, Slezicki Katherine I, Young Stephen G, Véniant Murielle, Dichek David A
机构信息
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, USA.
出版信息
Circulation. 2004 May 4;109(17):2129-35. doi: 10.1161/01.CIR.0000127369.24127.03. Epub 2004 Apr 19.
BACKGROUND
Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages.
METHODS AND RESULTS
To test the hypothesis that macrophage-expressed uPA contributes to the progression and complications of atherosclerosis, we generated transgenic mice with macrophage-targeted overexpression of uPA. The uPA transgene was bred into the apolipoprotein E-null background, and transgenic mice and nontransgenic littermate controls were fed an atherogenic diet. uPA-transgenic mice had significantly elevated uPA activity in the atherosclerotic artery wall, of a magnitude similar to elevations reported in atherosclerotic human arteries. Compared with littermate controls, uPA-transgenic mice had accelerated atherosclerosis, dilated aortic roots, occlusive proximal coronary artery disease, myocardial infarcts, and early mortality.
CONCLUSIONS
These data support the hypothesis that overexpression of uPA by artery wall macrophages is atherogenic and suggest that uPA inhibitors might be therapeutically useful.
背景
人类动脉粥样硬化病变中尿激酶型纤溶酶原激活剂（uPA）水平升高，主要由巨噬细胞表达。
方法与结果
为了验证巨噬细胞表达的uPA促进动脉粥样硬化进展和并发症发生这一假说，我们构建了巨噬细胞靶向性过表达uPA的转基因小鼠。将uPA转基因培育到载脂蛋白E基因缺失背景中，给转基因小鼠和同窝出生的非转基因对照小鼠喂食致动脉粥样化饮食。uPA转基因小鼠动脉粥样硬化动脉壁中的uPA活性显著升高，其升高幅度与人类动脉粥样硬化动脉中报道的升高幅度相似。与同窝对照相比，uPA转基因小鼠的动脉粥样硬化加速、主动脉根部扩张、近端冠状动脉闭塞性疾病、心肌梗死以及早期死亡。
结论
这些数据支持动脉壁巨噬细胞过表达uPA具有致动脉粥样化作用这一假说，并提示uPA抑制剂可能具有治疗用途。
Zotero 插件