This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 109/17/2129    most recent 01.CIR.0000127369.24127.03v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cozen, A. E. Articles by Dichek, D. A. Search for Related Content PubMed PubMed Citation Articles by Cozen, A. E. Articles by Dichek, D. A. Related Collections Animal models of human disease Pathophysiology Genetically altered mice Fibrinolysis

(Circulation. 2004;109:2129-2135.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Macrophage-Targeted Overexpression of Urokinase Causes Accelerated Atherosclerosis, Coronary Artery Occlusions, and Premature Death

Aaron E. Cozen, BA; Hideaki Moriwaki, MD, PhD; Michal Kremen, MD; Mary Beth DeYoung, PhD; Helén L. Dichek, MD; Katherine I. Slezicki; Stephen G. Young, MD; Murielle Véniant, PhD; David A. Dichek, MD

From the Gladstone Institute of Cardiovascular Disease, University of California, San Francisco (A.E.C., H.M., M.B.D., S.G.Y., M.V., D.A.D.) and the Departments of Medicine (H.M., M.K., K.I.S., D.A.D.) and Pediatrics (H.L.D.), University of Washington School of Medicine, Seattle.

Correspondence to David A. Dichek, MD, University of Washington School of Medicine, 1959 NE Pacific St, Box 357710, Seattle, WA 98195-7710. E-mail ddichek{at}u.washington.edu

Received April 11, 2003; de novo received October 17, 2003; revision received January 23, 2004; accepted January 27, 2004.

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.

Key Words: urokinase • atherosclerosis • coronary disease

This article has been cited by other articles:

				B. Fuhrman, J. Khateeb, M. Shiner, O. Nitzan, R. Karry, N. Volkova, and M. Aviram Urokinase Plasminogen Activator Upregulates Paraoxonase 2 Expression in Macrophages Via an NADPH Oxidase-Dependent Mechanism Arterioscler. Thromb. Vasc. Biol., July 1, 2008; 28(7): 1361 - 1367. [Abstract] [Full Text] [PDF]

				I. Yamaguchi, J. M. Lopez-Guisa, X. Cai, S. J. Collins, D. M. Okamura, and A. A. Eddy Endogenous urokinase lacks antifibrotic activity during progressive renal injury Am J Physiol Renal Physiol, July 1, 2007; 293(1): F12 - F19. [Abstract] [Full Text] [PDF]

				W. P. Fay, N. Garg, and M. Sunkar Vascular Functions of the Plasminogen Activation System Arterioscler. Thromb. Vasc. Biol., June 1, 2007; 27(6): 1231 - 1237. [Abstract] [Full Text] [PDF]

				K. Ohwaki, H. Bujo, M. Jiang, H. Yamazaki, W. J. Schneider, and Y. Saito A Secreted Soluble Form of LR11, Specifically Expressed in Intimal Smooth Muscle Cells, Accelerates Formation of Lipid-Laden Macrophages Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1050 - 1056. [Abstract] [Full Text] [PDF]

				A. Stempien-Otero, A. Plawman, J. Meznarich, T. Dyamenahalli, G. Otsuka, and D. A. Dichek Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator J. Biol. Chem., June 2, 2006; 281(22): 15345 - 15351. [Abstract] [Full Text] [PDF]

				A. Ponten, E. Bergsten Folestad, K. Pietras, and U. Eriksson Platelet-Derived Growth Factor D Induces Cardiac Fibrosis and Proliferation of Vascular Smooth Muscle Cells in Heart-Specific Transgenic Mice Circ. Res., November 11, 2005; 97(10): 1036 - 1045. [Abstract] [Full Text] [PDF]

				S. Zhang, M. H. Picard, E. Vasile, Y. Zhu, R. L. Raffai, K. H. Weisgraber, and M. Krieger Diet-Induced Occlusive Coronary Atherosclerosis, Myocardial Infarction, Cardiac Dysfunction, and Premature Death in Scavenger Receptor Class B Type I-Deficient, Hypomorphic Apolipoprotein ER61 Mice Circulation, June 28, 2005; 111(25): 3457 - 3464. [Abstract] [Full Text] [PDF]

				P. C. Schulze and R. T. Lee Macrophage-Mediated Cardiac Fibrosis Circ. Res., September 17, 2004; 95(6): 552 - 553. [Full Text] [PDF]

				H. Moriwaki, A. Stempien-Otero, M. Kremen, A. E. Cozen, and D. A. Dichek Overexpression of Urokinase by Macrophages or Deficiency of Plasminogen Activator Inhibitor Type 1 Causes Cardiac Fibrosis in Mice Circ. Res., September 17, 2004; 95(6): 637 - 644. [Abstract] [Full Text] [PDF]