title: Molecular signaling involved in oxysterol-induced β₁-integrin over-expression in human macrophages.
abstract: The hypercholesterolemia-atherosclerosis association is now established; hypercholesterolemia may induce vascular-cell activation, subsequently increasing expression of adhesion molecules, cytokines, chemokines, growth factors, and other key inflammatory molecules. Among inflammatory molecules expressed by vascular cells, integrins play a critical role in regulating macrophage activation and migration to the site of inflammation, by mediating cell-cell and cell-extracellular matrix interactions. The main lipid oxidation products present in oxidized LDL that may be responsible for inflammatory processes in atherogenesis, are cholesterol oxidation products, known as oxysterols. This study demonstrates the effect of an oxysterol mixture, compatible with that detectable in human hypercholesterolemic plasma, on the expression and synthesis of β(1)-integrin in cells of the macrophage lineage. The molecular signaling whereby oxysterols induce β(1)-integrin up-regulation is also comprehensively investigated. Over-expression of β(1)-integrin depends on activation of classic and novel members of protein kinase C and extracellular signal-regulated kinases 1 and 2, as well as of the up-stream G-protein (Gq and G13), c-Src, and phospholipase C. In addition, the localization of β(1)-integrin in advanced human carotid plaques is highlighted, marking its importance in atherosclerotic plaque progression.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Regione Gonzole 10, Orbassano 10043, Turin, Italy. giuseppe.poli@unito.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Gargiulo
authors.forename: Paola
authors.initials: P
authors.lastname: Gamba
authors.forename: Gabriella
authors.initials: G
authors.lastname: Testa
authors.forename: Barbara
authors.initials: B
authors.lastname: Sottero
authors.forename: Marco
authors.initials: M
authors.lastname: Maina
authors.forename: Tina
authors.initials: T
authors.lastname: Guina
authors.forename: Fiorella
authors.initials: F
authors.lastname: Biasi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Poli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Leonarduzzi
mesh_terms: D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013256:Steroids / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D019012:Integrin beta1; D013256:Steroids; D016392:Proto-Oncogene Proteins pp60(c-src); D011493:Protein Kinase C; D054801:Phosphoinositide Phospholipase C; D019204:GTP-Binding Proteins