Overexpression of urokinase by plaque macrophages causes histological features of plaque rupture and increases vascular matrix metalloproteinase activity in aged apolipoprotein e-null mice.
Overexpression of urokinase by plaque macrophages causes histological features of plaque rupture and increases vascular matrix metalloproteinase activity in aged apolipoprotein e-null mice.
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DOI：
10.1161/circulationaha.109.914945
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发表时间：
2010-04-13
期刊：
影响因子：
37.8
通讯作者：
Dichek DA
中科院分区：
文献类型：
--
作者：
Hu JH;Du L;Chu T;Otsuka G;Dronadula N;Jaffe M;Gill SE;Parks WC;Dichek DA
The mechanisms of atherosclerotic plaque rupture are poorly understood. Urokinase-type plasminogen activator (uPA) is expressed at elevated levels by macrophages in advanced human plaques. Patients with evidence of increased plasminogen activation have an elevated risk of major cardiovascular events. We used atherosclerotic mice to test the hypothesis that increased macrophage uPA expression in advanced plaques would cause histologic features similar to those in ruptured human plaques. Bone marrow from transgenic mice with increased macrophage uPA expression or nontransgenic controls (all Apoe−/−) was transplanted into 35-wk-old Apoe−/− recipients, and innominate lesions and aortae examined 8 – 13 wk later. Donor macrophages accumulated in innominate lesions adjacent to plaque caps and in aortae, increasing uPA expression at both sites. Recipients of uPA-overexpressing macrophages had an increased prevalence of intraplaque hemorrhage (61 vs 13%; P = 0.002) as well as increased lesion fibrin staining and fibrous cap disruption (P = 0.06 for both). Transplantation of uPA-overexpressing macrophages increased aortic matrix metalloproteinase (MMP) activity (40%; P = 0.02). This increase was independent of MMP-9. In advanced plaques of Apoe−/− mice, macrophage uPA overexpression causes intraplaque hemorrhage and fibrous cap disruption, features associated with human plaque rupture. uPA overexpression also increases vascular MMP activity. These data provide a mechanism that connects macrophage uPA expression, MMP activity, and plaque rupture features in mice. The data also suggest that elevated plaque plasminogen activator expression and plasminogen activation in humans may be causally linked to plaque rupture and cardiovascular events.
