Abstract
ObjectiveAtherosclerosis, a chronic inflammatory disease, arises from metabolic disorders and is driven by inappropriate recruitment and proliferation of monocytes / macrophages and vascular smooth-muscle-cells. The receptor for the urokinase-type plasminogen activator (uPAR, Plaur) regulates the proteolytic activation of plasminogen. It is also a coactivator of integrins and facilitates leukocyte-endothelial interactions and vascular smooth-muscle-cell migration. The role of uPAR in atherogenesis remains elusive.Methods and ResultsWe generated C57Bl6/J low-density lipoprotein receptor (LDL) and uPAR double knockout (uPAR-/-/LDLR-/-) mice to test the role of uPAR in two distinct atherosclerosis models. In LDLR-/- mice, hepatic overexpression following hydrodynamic transfection of soluble uPAR that competes with endogenous membrane-bound uPAR was performed as an interventional strategy. Aortic root atherosclerotic lesions induced by feeding a high-fat diet were smaller and comprised less macrophages and vascular smooth-muscle-cells in double knockout mice and animals overexpressing soluble uPAR when compared to controls. In contrast, lesion size, lipid-, macrophage-, and vascular smooth muscle cell content of guide-wire-induced intima lesions in the carotid artery were not affected by uPAR deficiency. Adhesion of uPAR-/--macrophages to TNFα-stimulated endothelial cells was decreased in vitro accompanied by reduced VCAM-1 expression on primary endothelial cells. Hepatic overexpression of soluble full-length murine uPAR in LDLR-/- mice led to a reduction of diet-induced atherosclerotic lesion formation and monocyte recruitment into plaques. Ex vivo incubation with soluble uPAR protein also inhibited adhesion of macrophages to TNFα-stimulated endothelial cells in vitro.ConclusionuPAR-deficiency as well as competitive soluble uPAR reduced diet-promoted but not guide-wire induced atherosclerotic lesions in mice by preventing monocyte recruitment and vascular smooth-muscle-cell infiltration. Soluble uPAR may represent a therapeutic tool for the modulation of hyperlipidemia-associated atherosclerotic lesion formation.
Highlights
Atherosclerosis is an inflammatory disease of the vessel wall characterized by monocyte recruitment to lesion-prone sites and their dedifferentiation into foam cells.[1, 2] Macrophages and vascular smooth muscle cells (VSMC) in the lesion release inflammatory mediators and proteolytic activity driving lesion progression.[3]
We generated C57Bl6/J low-density lipoprotein receptor (LDL) and uPAR double knockout mice to test the role of uPAR in two distinct atherosclerosis models
In LDLR-/- mice, hepatic overexpression following hydrodynamic transfection of soluble uPAR that competes with endogenous membrane-bound uPAR was performed as an interventional strategy
Summary
Atherosclerosis is an inflammatory disease of the vessel wall characterized by monocyte recruitment to lesion-prone sites and their dedifferentiation into foam cells.[1, 2] Macrophages and vascular smooth muscle cells (VSMC) in the lesion release inflammatory mediators and proteolytic activity driving lesion progression.[3]. Using the low-density lipoprotein-receptor deficiency (LDLR-/-)-[15] and Westerndiet-induced model of dyslipidemia and atherosclerosis, we analysed the effect of uPAR-deficiency on atherogenesis by comparing uPAR’s role for i) diet-induced spontaneous aortic root atherosclerosis and ii) guide-wire injury (GWI) induced intimal hyperplasia in the carotid artery. In a therapeutic approach, we investigated the impact of hepatic overexpression of soluble uPAR (suPAR) as competitive inhibitor of endogenous membrane bound uPAR in diet-induced atherosclerosis in LDL-receptor-deficient mice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
