Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation

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Abstract
The molecular mechanisms predisposing to atherosclerotic aneurysm formation remain undefined%1,5. Nevertheless, rupture of aortic aneurysms is a major cause of death in Western societies, with few available treatments and poor long-term progno–sis. Indirect evidence suggests that matrix metalloproteinases (MMPs) and plasminogen activators (PAs) are involved in its pathogenesis%1,6–12. MMPs are secreted as inactive zymogens (pro-MMPs), requiring activation in the extracellular compartment%11,13. Plasmin, generated from the zymogen plasminogen by tissue-type plasminogen activator (t-PA) or urokinase-type plas-minogen activator (u-PA; refs 14,15), has been proposed as a pos–sible activator in vitro, but evidence for such a role in vivo is lacking%16,17. Analysis of atherosclerotic aorta in mice with a deficiency of apoliprotein E (Apoe−/− ref. 18), singly or combined with a deficiency of t-PA (Apoe−/−.PIar−/−) or of u-PA (Apoe−/−-iPlair−/−, ref. 19), indicated that deficiency of u-PA protected against media destruction and aneurysm formation, probably by means of reduced plasmin-dependent activation of pro-MMPs. This genetic evidence suggests that plasmin is a pathophysiologically signifi–cant activator of pro-MMPs in vivo and may have implications for the design of therapeutic strategies to prevent aortic-wall destruction by controlling Plau gene function.