期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 44, 页码 17109-17114出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0808650105
关键词
proteolysis; aorta; aneurysm
资金
- National Heart, Lung, and Blood Institute [R01 HL080597, T32 HL07828, K08 HL070941]
- John L. Locke, Jr. Charitable Trust
Urokinase-type plasminogen activator (uPA) is expressed at elevated levels in atherosclerotic human arteries, primarily in macrophages. Plasminogen (Pig), the primary physiologic substrate of uPA, is present at significant levels in blood and interstitial fluid. Both uPA and Pig have activities that could affect atherosclerosis progression. Moreover, corrrelations between increased Pig activation and accelerated atherosclerosis are reported in several human studies. However, a coherent picture of the role of the uPA/PIg system in atherogenesis has not yet emerged, with at least one animal study suggesting that PIg is atheroprotective. We used a transgenic mouse model of macrophage-targeted uPA overexpression in apolipoprotein E-deficient mice to investigate the roles of uPA and Pig in atherosclerosis. We found that macrophage-expressed uPA accelerated atherosclerotic plaque growth and promoted aortic root dilation through Pig-dependent pathways. These pathways appeared to affect lesion progression rather than initiation and to include actions that disproportionately increase lipid accumulation in the artery wall. In addition, loss of Pig was protective against atherosclerosis both in the presence and absence of uPA overexpression. Transgenic mice with macrophage-targeted uPA overexpression reveal atherogenic roles for both uPA and Pig and are a useful experimental setting for investigating the molecular mechanisms that underlie clinically established relationships between uPA expression, Pig activation, and atherosclerosis progression.
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