Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation

Nat Genet. 1997 Dec;17(4):439-44. doi: 10.1038/ng1297-439.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Aneurysm, Abdominal / enzymology*
  • Aortic Aneurysm, Abdominal / etiology
  • Aortic Aneurysm, Abdominal / pathology
  • Aortic Aneurysm, Thoracic / enzymology*
  • Aortic Aneurysm, Thoracic / etiology
  • Aortic Aneurysm, Thoracic / pathology
  • Arteriosclerosis / enzymology
  • Arteriosclerosis / pathology
  • Collagen / metabolism
  • Diet, Atherogenic
  • Elastin / metabolism
  • Enzyme Activation
  • Female
  • Fibrinolysin / metabolism*
  • Macrophages / enzymology
  • Male
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Knockout
  • Tunica Media / enzymology
  • Tunica Media / pathology
  • Urokinase-Type Plasminogen Activator / metabolism*


  • Collagen
  • Elastin
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator
  • Metalloendopeptidases