Abstract 1714: Loss of Urokinase Plasminogen Activator Expression in Macrophages Retards Aortic Atherosclerosis in Apolipoprotein E-Null Mice
Background Apolipoprotein E-null mice (Apoe−/−) with a macrophage-targeted urokinase (uPA) transgene (SR-uPA+/0Apoe−/− ) have accelerated atherosclerosis (athero), severe coronary stenoses, and premature death. Moreover, transplantation of bone marrow (BM) from SR-uPA+/0Apoe−/− mice accelerates lesion progression in nontransgenic Apoe−/− recipients.
Hypothesis We hypothesized that macrophage-expressed uPA is an important modifier of athero, and that transplantation of uPA-deficient BM would retard athero.
Methods BM from uPA-deficient (Plau−/−) or uPA wildtype (Plau+/+) mice was transplanted into 8-wk-old Plau+/+/mice. All were C57BL6 Apoe−/− mice. Experimental donor: Plau−/−Apoe−/− ; Recipient: Plau+/+ Apoe−/− Control donor: Plau+/+Apoe−/− ; Recipient: Plau+/+Apoe−/− The recipients were started on a Western diet at 12 wks of age and euthanized at 37 wks. Plasma lipid levels, FPLC profiles, and peripheral blood monocyte counts were obtained by standard methods. Athero was quantified by en face analysis of pinned whole aortas and using H&E-stained aortic root sections. Lipid content in aortic root plaques was measured by oil red O (ORO) staining.
Results Plasma lipids, FPLC profiles and peripheral blood monocytes were not affected by loss of macrophage uPA expression. En face analysis of aortae revealed 35% less plaque area in recipients of Plau−/− BM than in recipients of Plau+/+BM (21 ± 10 vs 31 ± 13%; P =0.034). This difference appeared to be more pronounced in abdominal aorta, where lesions are at an earlier stage. However, recipients of Plau−/− BM had similar aortic root plaque area (0.7 ± 0.23 vs 0.6 ± 0.22 mm2; P=0.3) and there was no change in total or percent ORO area of aortic root plaques (58 ± 5 vs 57 ± 9%; P=0.8).
Conclusion Loss of uPA expression by macrophages retards athero in whole aortas of 37-wk old Apoe−/− mice, but does not affect aortic root plaque area or lipid content. Overall, our results suggest that low levels of macrophage-expressed uPA may facilitate lesion initiation (as in the present study) whereas high levels accelerate lesion progression (results of our previous work with uPA-overexpressing SR-uPA+/0 mice and transplantation of their BM). Inhibition of uPA might retard both initiation and progression of athero.