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Title: Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation
Authors: Carmeliet, Peter ×
Moons, Lieve
Lijnen, Roger
Baes, Myriam
Lemaître, V
Tipping, P
Drew, A
Eeckhout, Y
Shapiro, S
Lupu, F
Collen, Desire #
Issue Date: Dec-1997
Series Title: Nature genetics vol:17 issue:4 pages:439-44
Abstract: The molecular mechanisms predisposing to atherosclerotic aneurysm formation remain undefined. 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. MMPs are secreted as inactive zymogens (pro-MMPs), requiring activation in the extracellular compartment. 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. 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.
URI: 
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
Cell Metabolism
Animal Physiology and Neurobiology Section - miscellaneous
Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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