Abstract 1713: Urokinase Receptor-Deficiency Reduces Spontaneous Atherosclerosis in LDL-receptor-deficient Mice
Introduction: Atherosclerosis is an inflammatory disease of the vessel wall characterized by enhanced leukocyte recruitment to lesion prone sites. The receptor of urokinase, uPAR, facilitates leukocyte-endothelial interactions. uPAR is highly expressed in human atheroscle-rotic lesions and expression correlates with severity of atherosclerosis. uPAR’s role in atherogenesis is uncertain. To clarify whether u-PAR alters lesion formation, we generated LDL receptor-uPAR double deficient mice that we subjected to two models for atherosclerosis: spontaneous aortic valve (VA) and accelerated atherosclerosis after carotid guide wire de-endothelialization (GWI).
Methods: Age and sex matched uPAR−/−/LDLR−/− and uPAR+/+-LDLR−/− control mice were generated by breeding. Mice (12 w) were fed a high-fat/high cholesterol/no cholate diet for 10w before aortic roots were harvested. Plasma lipid levels were determined colorimetrically. A separate group of mice was subjected to GWI after 6w of diet and 4 w before harvest of injured left and right control carotid arteries. Lesions were morphometrically analyzed on 5 μm sections of oil red-O or macrophage (MAC3) stained aortic valves or carotids as % lesion or macrophage area of total lumen area. Data are presented as mean±SD and tested non-parametrically.
Results: Feeding induced similar hyperlipidemia in both groups (TC: uPAR−/−/LDLR−/−:75+/−20mg/dl vs 347+/−285mg/dl, uPAR+/+-LDLR−/ −:88+/−20mg/dl vs 365+/−167mg/dl; bsl vs 6 weeks). uPAR−/ −LDLR−/ − had significantly smaller VA-lesions compared to controls (9+/−2.5% vs 15.5+/−4.8%, n=11, p<0.05) and less macrophages (11.3+/−2.7% vs 15.7+/−2.9%, n=11, p<0.05). GWI induced lesions in the carotid of both genotypes with no differences in lesion area or macrophages.
Discussion: uPAR-deficiency reduces spontaneous endothelium-dependent atherosclerotic VA-lesion formation of mice, while endothelium-independent accelerated atherosclerosis is not sensitive to u-PAR. u-PAR-deficiency reduces macrophage content of VA-lesions but does not affect carotid lesions. u-PAR importantly contributes to macrophage recruitment into the vessel wall during atherogenesis and a potential therapeutic target.