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Absence of uPAR Protects against the Development of Atherosclerosis in LDL Receptor-Null Mice

Srinivasa T Reddy

We have previously identified unrokinase plasminogen activator receptor [uPAR] as one of several genes differentially induced in human aortic endothelial cells [HAEC] by Oxidized-L-alpha-1-Palmitoyl-2-Arachidonoyl-snglycero- 3-Phosphorylcholine [Ox-PAPC], which is a key biologically active component oxidized low-density lipoprotein [Ox-LDL]. The role of uPAR in the development of atherosclerosis is not known. In this report, we show that uPAR message and protein are induced in HAEC within hours of Ox-PAPC treatment. We developed uPAR-/- mice on an LDLR-/- background [uPAR-/-/LDLR-/-] and show that uPAR plays a proatherogenic role in the aortic vascular milieu. When compared to LDLR-/- mice, uPAR-/-/LDLR-/- mice fed a Western diet for 12 weeks had i] an anti-atherogenic serum lipid profile, ii] less atherogenic lipoproteins, iii] reduced accumulation of macrophages in the aortic sinus lesions, and iv] significantly reduced atherosclerosis in the entire aortic tree and the aortic sinus. Our results suggest, for the first time, that uPAR inhibition is a potential therapeutic approach to prevent atherosclerosis development.