Lack of urokinase plasminogen activator promotes progression and instability of atherosclerotic lesions in apolipoprotein E-knockout mice.
Urokinase plasminogen activator (uPA) is strongly expressed in atherosclerotic lesions, but the overall effect of the protease on plaque composition and growth remains controversial. In the present study, apolipoprotein E-deficient (apoE(-/-)) mice were intercrossed with mice which were lacking the uPA gene (doubleknockout; DKO). In ferric chloride-induced carotid artery lesions in chow-fed mice, uPA deficiency increased neointimal size (P = 0.015) and luminal stenosis (P = 0.014), while reducing media thickness (P = 0.002). A lack of uPA also increased the size of and the luminal obstruction from atherosclerotic plaques at the coronary and brachiocephalic arteries of apoE(-/-) mice. Plaques were characterised by a higher fibrinogen/fibrin content and a decrease in cellularity and collagen content. When apoE(-/-) and DKO mice were analysed as a single group, a significant correlation was found between the alpha-actin (smooth muscle cell) and collagen content of atherosclerotic lesions (r = 0.554; P < 0.05), and a negative correlation existed between the alpha-actin and fibrin/fibrinogen immunopositive area (r = -0.791; P < 0.001). Further analysis of brachiocephalic atherosclerosis, a predilection site for plaque rupture in the apoE(-/-) mouse, revealed signs of plaque vulnerability, including a reduced cap-to-intima ratio (0.21 +/- 0.04 vs. 0.37 +/- 0.05; P = 0.03) and more frequent detection of intraplaque haemorrhage (56% vs. 13%; P < 0.01) and buried fibrous caps (1.8 +/- 0.5 vs. 0.5 +/- 0.2; P = 0.02) in DKO compared to apoE(-/-) mice. These results indicate that, at least at (patho)physiologic concentrations, uPA is essential for maintaining the cellularity and collagen content and, possibly, the stability of lesions, both by preventing excessive intramural fibrin accumulation and by facilitating cell migration and invasion.
Dellas
Claudia
C
Department of Cardiology and Pulmonology, Georg August University School of Medicine, Robert-Koch-Strasse 40, 37099 Goettingen, Germany.
Schremmer
Carmen
C
Hasenfuss
Gerd
G
Konstantinides
Stavros V
SV
Schäfer
Katrin
K
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology*; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology*; D002340:Carotid Artery Diseases; D002465:Cell Movement; D003094:Collagen / Q000032:analysis; D018450:Disease Progression; D005337:Fibrin / Q000032:analysis; D006470:Hemorrhage; D051379:Mice; D018345:Mice, Knockout; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency*
D001057:Apolipoproteins E; D005337:Fibrin; D003094:Collagen; D014568:Urokinase-Type Plasminogen Activator