Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation
(1997) Nature Genetics — Vol. 17, n° 4, p. 439-444 (1997)
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- 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 prognosis. 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 plasminogen activator (u-PA; refs 14,15), has been proposed as a possible 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(-/-):Plat(-/-)) or of u-PA (Apoe(-/-):Plau(-/-); 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 significant 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.
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Carmeliet, P., Moons, L., Lijnen, R., Baes, M., Lemaitre, V., Tipping, P., Drew, A., Eeckhout, Y., Shapiro, S., Lupu, F., & Collen, D. (1997). Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nature Genetics, 17(4), 439-444. https://doi.org/10.1038/ng1297-439 (Original work published 1997)