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Molecular Signaling Involved in Oxysterol-Induced β1-Integrin Over-Expression in Human Macrophages
Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, Regione Gonzole 10, Orbassano 10043, Turin, Italy
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 10 September 2012; in revised form: 24 October 2012 / Accepted: 25 October 2012 / Published: 5 November 2012
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 β1-integrin in cells of the macrophage lineage. The molecular signaling whereby oxysterols induce β1-integrin up-regulation is also comprehensively investigated. Over-expression of β1-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 β1-integrin in advanced human carotid plaques is highlighted, marking its importance in atherosclerotic plaque progression.
Keywords: atherosclerosis; oxysterols; β1-integrin; cell signaling
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Gargiulo, S.; Gamba, P.; Testa, G.; Sottero, B.; Maina, M.; Guina, T.; Biasi, F.; Poli, G.; Leonarduzzi, G. Molecular Signaling Involved in Oxysterol-Induced β1-Integrin Over-Expression in Human Macrophages. Int. J. Mol. Sci. 2012, 13, 14278-14293.
Gargiulo S, Gamba P, Testa G, Sottero B, Maina M, Guina T, Biasi F, Poli G, Leonarduzzi G. Molecular Signaling Involved in Oxysterol-Induced β1-Integrin Over-Expression in Human Macrophages. International Journal of Molecular Sciences. 2012; 13(11):14278-14293.
Gargiulo, Simona; Gamba, Paola; Testa, Gabriella; Sottero, Barbara; Maina, Marco; Guina, Tina; Biasi, Fiorella; Poli, Giuseppe; Leonarduzzi, Gabriella. 2012. "Molecular Signaling Involved in Oxysterol-Induced β1-Integrin Over-Expression in Human Macrophages." Int. J. Mol. Sci. 13, no. 11: 14278-14293.