title: Hepatic Overexpression of Soluble Urokinase Receptor (uPAR) Suppresses Diet-Induced Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient (LDLR-/-) Mice.
abstract: OBJECTIVE
  Atherosclerosis, 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  uPAR-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.
authors: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany; Department of Anesthesiology University Hospital Heidelberg, Heidelberg, Germany.
authors: Jan
authors: J
authors: Larmann
authors: Center for Thrombosis and Hemostasis (CTH), University Medical Center, Mainz, Germany.
authors: Kerstin
authors: K
authors: Jurk
authors: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors: Henrike
authors: H
authors: Janssen
authors: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors: Martin
authors: M
authors: Müller
authors: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors: Christine
authors: C
authors: Herzog
authors: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
authors: Anika
authors: A
authors: Lorenz
authors: Institute for Anatomy, University of Münster, Münster, Germany.
authors: Martina
authors: M
authors: Schmitz
authors: Center for Laboratory Medicine, University Hospital Münster, Münster, Germany.
authors: Jerzy-Roch
authors: JR
authors: Nofer
authors: Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany; Department of Health Services Sciences, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany.
authors: Gregor
authors: G
authors: Theilmeier
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D011973:Receptors, LDL; D055293:Receptors, Urokinase Plasminogen Activator