Level of macrophage uPA expression is an important determinant of atherosclerotic lesion growth in Apoe-/- mice.
OBJECTIVE
Enhanced plasminogen activation, mediated by overexpression of urokinase-type plasminogen activator (uPA), accelerates atherosclerosis in apolipoprotein E-null mice. However, the mechanisms through which uPA acts remain unclear. In addition, although elevated uPA expression can accelerate murine atherosclerosis, there is not yet any evidence that decreased uPA expression would retard atherosclerosis.


RESULTS
We used a bone marrow transplant (BMT) approach and apolipoprotein E-deficient (Apoe(-/-)) mice to investigate cellular mechanisms of uPA-accelerated atherosclerosis, aortic dilation, and sudden death. We also used BMT to determine whether postnatal loss of uPA expression in macrophages retards atherosclerosis. BMT from uPA-overexpressing mice yielded recipients with macrophage-specific uPA overexpression; whereas BMT from uPA knockout mice yielded recipients with macrophage-specific loss of uPA expression. Recipients of uPA-overexpressing BM acquired all the vascular phenotypes (accelerated atherosclerosis, aortic medial destruction and dilation, severe coronary stenoses) as well as the sudden death phenotype of uPA-overexpressing mice. Moreover, fat-fed 37-week-old recipients of uPA-null BM had significantly less atherosclerosis than recipients of uPA wild-type marrow (40% less aortic surface lesion area; P=0.03).


CONCLUSIONS
The level of uPA expression by macrophages-over a broad range-is an important determinant of atherosclerotic lesion growth in Apoe(-/-) mice.
Krishnan
Ranjini
R
Department of Medicine, University of Washington, Seattle, WA 98195-7710, USA.
Kremen
Michal
M
Hu
Jie Hong
JH
Emery
Isaac
I
Farris
Stephen D
SD
Slezicki
Katherine I
KI
Chu
Talyn
T
Du
Liang
L
Dichek
Helén L
HL
Dichek
David A
DA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D001057:Apolipoproteins E; D015415:Biomarkers; D014568:Urokinase-Type Plasminogen Activator