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.
Highlights
Atherosclerosis is a progressive degenerative process of the arterial blood vessels that is characterized by the accumulation of lipids and fibrous elements in the large and medium arteries.it is a multifactorial and multiphasic disease
In order to investigate the presence of β1-integrin in human atherosclerotic lesions, sections of human carotid plaques were used for immunohistochemical analyses
The β1-integrin production in the intima should co-localize with macrophages which are the major cells present in the core region while smooth muscle cells should be responsible for its production within the media
Summary
Atherosclerosis is a progressive degenerative process of the arterial blood vessels that is characterized by the accumulation of lipids and fibrous elements in the large and medium arteries. It is a multifactorial and multiphasic disease. Monocyte recruitment is a multistep process mediated by adhesion molecules It begins with rolling, mediated by short-lived bonds between E-selectin on endothelial cells (EC) and sialylated ligands such as P-selectin glycoprotein ligand 1 on monocytes, followed by firm arrest, through interactions between activated β1- and β2-integrins on monocytes with vascular-cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) on EC. Arrested monocytes undergo transmigration through the endothelial monolayer, and subsequent migration through the extracellular matrix (ECM) [2,3]
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