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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1737.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Level of Macrophage uPA Expression Is an Important Determinant of Atherosclerotic Lesion Growth in Apoe^–/– Mice

Ranjini Krishnan; Michal Kremen; Jie Hong Hu; Isaac Emery; Stephen D. Farris; Katherine I. Slezicki; Talyn Chu; Liang Du; Helén L. Dichek; David A. Dichek

From the Departments of Medicine (R.K., M.K., J.H.H., I.E., S.D.F., K.I.S., T.C., L.D., D.A.D.) and Pediatrics (H.L.D.), University of Washington, Seattle.

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

Objective— Enhanced plasminogen activation, mediated by overexpression of urokinase-type plasminogen activator (uPA), accelerates atherosclerosis in apolipoprotein E–null mice. However, the mechanisms through which uPA acts remain unclear. In addition, although elevated uPA expression can accelerate murine atherosclerosis, there is not yet any evidence that decreased uPA expression would retard atherosclerosis.

Methods and Results— We used a bone marrow transplant (BMT) approach and apolipoprotein E–deficient (Apoe^–/–) mice to investigate cellular mechanisms of uPA-accelerated atherosclerosis, aortic dilation, and sudden death. We also used BMT to determine whether postnatal loss of uPA expression in macrophages retards atherosclerosis. BMT from uPA-overexpressing mice yielded recipients with macrophage-specific uPA overexpression; whereas BMT from uPA knockout mice yielded recipients with macrophage-specific loss of uPA expression. Recipients of uPA-overexpressing BM acquired all the vascular phenotypes (accelerated atherosclerosis, aortic medial destruction and dilation, severe coronary stenoses) as well as the sudden death phenotype of uPA-overexpressing mice. Moreover, fat-fed 37-week-old recipients of uPA-null BM had significantly less atherosclerosis than recipients of uPA wild-type marrow (40% less aortic surface lesion area; P=0.03).

Conclusions— The level of uPA expression by macrophages—over a broad range—is an important determinant of atherosclerotic lesion growth in Apoe^–/– mice.

We generated mice with either macrophage-specific overexpression of urokinase (uPA) or macrophage-specific loss of uPA. Macrophage uPA overexpression accelerated atherosclerosis and macrophage uPA deletion retarded atherosclerosis. The level of macrophage uPA expression—over a broad range—is an important determinant of atherosclerotic lesion growth in Apoe^–/– mice.

Key Words: urokinase • macrophages • atherosclerosis • aneurysm • bone marrow transplant