Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation.
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.
Carmeliet
P
P
Centre for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Belgium.
Moons
L
L
Lijnen
R
R
Baes
M
M
Lemaître
V
V
Tipping
P
P
Drew
A
A
Eeckhout
Y
Y
Shapiro
S
S
Lupu
F
F
Collen
D
D
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D004549:Elastin / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017540:Tunica Media / Q000201:enzymology / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D003094:Collagen; D004549:Elastin; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases