Molecular and cellular biology of the urokinase/urokinase receptor -related vascular remodeling: role in vascular inflammation

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This proposal addresses a role of the multifunctional urokinase receptor (uPAR) in vascular remodeling and inflammation. Our recent findings revealed one novel unexpected function for uPAR in these processes. We found that modified lipids initiate atherogenic signals triggering transition of vascular smooth muscle cells (VSMC) to pathophysiological phenotype and to expression of pro-inflammatory molecules. We provide evidence that uPAR was indispensable to mediate these effects. These findings point to yet unknown abilities of uPAR and modified lipids to affect vascular inflammation and remodeling by uncommon mechanisms. We observed uPAR structural and functional association with the pattern recognition receptors CD36 and TLR4 in response to oxLDL in VSMC. Though several interacting proteins have been identified for uPAR, its association neither with CD36 nor with TLR4 has been documented. These findings suggest complex of uPAR, CD36 and TLR4 as a functional cluster of pattern recognition receptors that recognizes and signals self-origin and most likely pathogen ligands and triggers inflammation. We hypothesize that, like lipopolysaccharide, the interaction of modified lipids with TLR4 may be enhanced by binding to a GPI-anchored protein. In VSMC, formation and activation of this functional unit in response to modified lipids may be a mechanism to trigger and propagate the atherogenic inflammation. Our data suggest that uPAR may govern specific inflammatory responses depending on its association with TLR4 or CD36 and function as a sensor for endogenous and exogenous pattern ligands. Identification of this molecular machinery and evaluation of its functional consequences in vivo represent the major goal of the present proposal. The expected results may provide additional new insights into the link among lipids, inflammation and atherosclerosis and further provide potential therapeutic or preventive targets for cardiovascular diseases.