Macrophage-targeted overexpression of urokinase causes accelerated atherosclerosis, coronary artery occlusions, and premature death

• Published in: Circulation (New York, N.Y.) Vol. 109; no. 17; pp. 2129 - 2135
• Main Authors: COZEN, Aaron E, MORIWAKI, Hideaki, KREMEN, Michal, DEYOUNG, Mary Beth, DICHEK, Helén L, SLEZICKI, Katherine I, YOUNG, Stephen G, VENIANT, Murielle, DICHEK, David A
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 04.05.2004
• Subjects: Animals; Aortic Diseases - enzymology; Aortic Diseases - genetics; Aortic Diseases - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arteriosclerosis - blood; Arteriosclerosis - enzymology; Arteriosclerosis - genetics; Arteriosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cholesterol - blood; Coronary Disease - enzymology; Coronary Disease - genetics; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enhancer Elements, Genetic - genetics; Female; Genes, Synthetic; Heat-Shock Proteins - genetics; Humans; Longevity - genetics; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myocardial Infarction - enzymology; Myocardial Infarction - genetics; Promoter Regions, Genetic - genetics; Receptors, Immunologic - genetics; Recombinant Fusion Proteins - physiology; Scavenger Receptors, Class A; Transgenes; Triglycerides - blood; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - physiology; Vascular disease; Premature; coronary disease; Coronary artery; Atherosclerosis; urokinase; Cardiovascular disease; Macrophage
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000127369.24127.03

Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages. 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. These data support the hypothesis that overexpression of uPA by artery wall macrophages is atherogenic and suggest that uPA inhibitors might be therapeutically useful.