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Circ Res. 2004 Sep 17;95(6):637-44. Epub 2004 Aug 5.

Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type 1 causes cardiac fibrosis in mice.

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  • 1Department of Medicine, University of Washington, Seattle, WA 98195-7710, USA.


Several studies implicate elevated matrix metalloproteinase activity as a cause of cardiac fibrosis. However, it is unknown whether other proteases can also initiate cardiac fibrosis. Because absence of urokinase plasminogen activator (uPA) prevents development of cardiac fibrosis after experimental myocardial infarction in mice, we hypothesized that elevated activity of uPA or deficiency of the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) might cause cardiac fibrosis. We used mice with scavenger-receptor (SR)-directed, macrophage-targeted uPA overexpression (SR-uPA+/0 mice) and PAI-1 null mice to test these hypotheses. Our studies revealed that SR-uPA+/0 mice developed cardiac fibrosis beginning between 5 and 10 weeks of age. Fibrosis was preceded by cardiac macrophage accumulation, implicating uPA-secreting macrophages as important contributors to development of fibrosis. A key role for uPA-secreting macrophages in development of cardiac fibrosis was supported by experiments in which recipients of bone marrow transplants from SR-uPA+/0 donors but not nontransgenic donors developed cardiac macrophage accumulation and fibrosis. SR-uPA+/0 mice and recipients of SR-uPA+/0 bone marrow had neither macrophage accumulation nor fibrosis in other major organs despite the presence of higher levels of uPA in these organs than in hearts. PAI-1 null mice but not congenic, age-matched controls also developed macrophage accumulation and fibrosis in hearts but not in other organs. We conclude: (1) either elevated macrophage uPA expression or PAI-1 deficiency is sufficient to cause cardiac macrophage accumulation and fibrosis; (2) macrophages are important contributors to the development of cardiac fibrosis; and (3) the heart is particularly sensitive to the effects of excess uPA activity.

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