Overexpression of Urokinase by Plaque Macrophages Causes Histological Features of Plaque Rupture and Increases Vascular Matrix Metalloproteinase Activity in Aged Apolipoprotein E–Null Mice

Background— 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 histological features similar to those in ruptured human plaques. Methods and Results— Bone marrow from transgenic mice with increased macrophage uPA expression or nontransgenic controls (all apolipoprotein E–null [Apoe−/−]) was transplanted into 35-week-old Apoe−/− recipients, and innominate lesions and aortas were examined 8 to 13 weeks later. Donor macrophages accumulated in innominate lesions adjacent to plaque caps and in aortas, increasing uPA expression at both sites. Recipients of uPA-overexpressing macrophages had an increased prevalence of intraplaque hemorrhage (6...