title: Reduced beta3-endonexin levels are associated with enhanced urokinase-type plasminogen activator receptor expression in ApoE-/- mice.
abstract: Proteolysis of extracellular matrix components is required for cell migration occurring in atherosclerotic lesion formation. In the present study, gene expression of the urokinase plasmingen activator receptor (uPAR) and underlying mechanisms were analyzed during the development of atherosclerosis in the aorta of apolipoprotein E-deficient mice (apoE(-/-)). A significant increase of uPAR expression was detected in the atherosclerotic tissue with advancing plaque-dimension. As uPAR gene transcription involves the transcription factor nuclear factor-kappaB (NF-kappaB), we analyzed nuclear NF-kappaB activity in vascular tissue of apoE-deficient mice. Congruent to uPAR, we could detect an increase in NF-kappaB activity, which underlines the chronic inflammatory component of the disease. Recently we reported that beta(3)-endonexin, a protein that modulates beta(3)-integrins, regulates uPAR expression through direct interaction with subunits of the NF-kappaB-complex. Herein we could show that beta(3)-endonexin protein is expressed in aortic tissue of mice. Moreover, in contrast to uPAR or NF-kappaB, the expression of beta(3)-endonexin was reduced in extracts of advanced atherosclerotic aortic tissue. The cytoplasmic protein beta(3)-endonexin regulates function of beta(3)-integrins. We revealed that integrin stimulation of endothelial cells led to an enhanced NF-kappaB activity and secretion of the NF-kappaB dependent chemokine monocyte chemoattractant protein-1 (MCP-1). The beta(3)-integrin dependent increase in MCP-1 was notedly reduced in cells that overexpressed beta(3)-endonexin. These results provide strong evidence that beta(3)-endonexin acts as a regulating factor in the integrin-mediated signal transduction and the present findings imply a pathophysiological role of beta(3)-endonexin in atherogenesis.
authors.affiliation: Deutsches Herzzentrum München, Lazarettstrasse 36, 80636 Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Besta
authors.forename: I
authors.initials: I
authors.lastname: Müller
authors.forename: M
authors.initials: M
authors.lastname: Lorenz
authors.forename: S
authors.initials: S
authors.lastname: Massberg
authors.forename: A
authors.initials: A
authors.lastname: Bültmann
authors.forename: N
authors.initials: N
authors.lastname: Cabeza
authors.forename: T
authors.initials: T
authors.lastname: Richter
authors.forename: E
authors.initials: E
authors.lastname: Kremmer
authors.forename: C
authors.initials: C
authors.lastname: Nothdurfter
authors.forename: K
authors.initials: K
authors.lastname: Brand
authors.forename: M
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000209:etiology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D039661:Integrin beta3 / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins; D011506:Proteins / Q000032:analysis / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C403295:ITGB3BP protein, human; D039661:Integrin beta3; D016328:NF-kappa B; D009687:Nuclear Proteins; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D011506:Proteins; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator