Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Pathogenesis of Atherosclerosis

Background:

• Aortic aneurysm rupture is a leading cause of mortality with limited treatment options.
• Matrix metalloproteinases (MMPs) and plasminogen activators (PAs) are implicated in aneurysm pathogenesis.
• The in vivo role of plasmin in activating MMPs for aneurysm formation is not well-established.

Purpose of the Study:

• To investigate the role of urokinase-type plasminogen activator (u-PA) in atherosclerotic aneurysm development.
• To determine if plasmin is a key in vivo activator of pro-MMPs in the context of atherosclerosis.

Main Methods:

• Analysis of atherosclerotic aorta in apolipoprotein E-deficient (Apoe-/-) mice.
• Comparison of Apoe-/- mice with deficiencies in tissue-type plasminogen activator (t-PA) or u-PA.
• Assessment of media destruction and aneurysm formation.

Main Results:

• Mice deficient in u-PA (Apoe-/-:Plau-/-) showed protection against aortic media destruction and aneurysm formation.
• This protection is likely due to reduced plasmin-dependent activation of pro-MMPs.
• Apoe-/-:Plat-/- mice did not show similar protection, implicating u-PA specifically.

Conclusions:

• Genetic evidence strongly suggests plasmin is a significant in vivo activator of pro-MMPs.
• u-PA plays a critical role in the pathogenesis of atherosclerotic aortic aneurysms.
• Targeting u-PA or plasmin activity may offer novel therapeutic strategies for preventing aortic wall destruction.