Macrophage-targeted overexpression of urokinase causes accelerated atherosclerosis, coronary artery occlusions, and premature death.
BACKGROUND
Human atherosclerotic lesions contain elevated levels of urokinase plasminogen activator (uPA), expressed predominantly by macrophages.


RESULTS
To test the hypothesis that macrophage-expressed uPA contributes to the progression and complications of atherosclerosis, we generated transgenic mice with macrophage-targeted overexpression of uPA. The uPA transgene was bred into the apolipoprotein E-null background, and transgenic mice and nontransgenic littermate controls were fed an atherogenic diet. uPA-transgenic mice had significantly elevated uPA activity in the atherosclerotic artery wall, of a magnitude similar to elevations reported in atherosclerotic human arteries. Compared with littermate controls, uPA-transgenic mice had accelerated atherosclerosis, dilated aortic roots, occlusive proximal coronary artery disease, myocardial infarcts, and early mortality.


CONCLUSIONS
These data support the hypothesis that overexpression of uPA by artery wall macrophages is atherogenic and suggest that uPA inhibitors might be therapeutically useful.
Cozen
Aaron E
AE
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, USA.
Moriwaki
Hideaki
H
Kremen
Michal
M
DeYoung
Mary Beth
MB
Dichek
Helén L
HL
Slezicki
Katherine I
KI
Young
Stephen G
SG
Véniant
Murielle
M
Dichek
David A
DA
D000818:Animals; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003327:Coronary Disease / Q000201:enzymology* / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D005813:Genes, Synthetic; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008136:Longevity / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D051117:Scavenger Receptors, Class A; D019076:Transgenes; D014280:Triglycerides / Q000097:blood; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D006360:Heat-Shock Proteins; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C112525:SCARA3 protein, human; D051117:Scavenger Receptors, Class A; D014280:Triglycerides; D002784:Cholesterol; D014568:Urokinase-Type Plasminogen Activator