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J. Biol. Chem., Vol. 281, Issue 22, 15345-15351, June 2, 2006

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Mechanisms of Cardiac Fibrosis Induced by Urokinase Plasminogen Activator^*

From the Department of Medicine, Division of Cardiology, University of Washington School of Medicine, Seattle, Washington, 98195

Human hearts with end-stage failure and fibrosis have macrophage accumulation and elevated plasminogen activator activity. However, the mechanisms that link macrophage accumulation and plasminogen activator activity with cardiac fibrosis are unclear. We previously reported that mice with macrophage-targeted overexpression of urokinase plasminogen activator (SR-uPA^+/o mice) develop cardiac macrophage accumulation by 5 weeks of age and cardiac fibrosis by 15 weeks. We used SR-uPA^+/o mice to investigate mechanisms through which macrophage-expressed uPA causes cardiac macrophage accumulation and fibrosis. We hypothesized that: 1) macrophage accumulation and cardiac fibrosis in SR-uPA^+/o mice are dependent on localization of uPA by the uPA receptor (uPAR); 2) activation of plasminogen by uPA and subsequent activation of transforming growth factor-1 (TGF-1) and matrix metalloproteinase (MMP)-2 and -9 by plasmin are critical pathways through which uPA-expressing macrophages accumulate in the heart and cause fibrosis; and 3) uPA-induced cardiac fibrosis can be attenuated by treatment with verapamil. To test these hypotheses, we bred the SR-uPA^+/o transgene into mice deficient in either uPAR or plasminogen and measured cardiac macrophage accumulation and fibrosis. We also measured cardiac TGF-1 protein (total and active), Smad2 phosphorylation, and MMP activity after the onset of macrophage accumulation but before the onset of cardiac fibrosis. Finally, we treated mice with verapamil. Our studies revealed that plasminogen is necessary for uPA-induced cardiac fibrosis and macrophage accumulation but uPAR is not. We did not detect plasmin-mediated activation of TGF-1, MMP-2, or MMP-9 in hearts of SR-uPA^+/o mice. However, verapamil treatment significantly attenuated both cardiac fibrosis and macrophage accumulation.

Received for publication, November 30, 2005 , and in revised form, March 7, 2006.

^* This work was supported by Grants HL70941 (to A. S.-O.) and HL080597 (to D. A. D.) from the National Institutes of Health and a grant from the Locke Family Foundation (to A. S.-O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Washington Medical Center, Box 357710, Seattle, WA 98195. Tel.: 206-616-9054; Fax: 206-221-6346; E-mail: april{at}u.washington.edu.

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