Arif Yurdagul1, Jonette Green1, Patrick Albert1, Marshall C McInnis1, Andrew P Mazar1, A Wayne Orr2. 1. From the Departments of Pathology (A.Y., J.G., P.A., M.C.M., A.W.O.) and Cell Biology and Anatomy (A.Y., A.W.O.), Louisiana State University Health Sciences Center, Shreveport; and Chemistry of Life Processes Institute, Northwestern University, Evanston, IL (A.P.M.). 2. From the Departments of Pathology (A.Y., J.G., P.A., M.C.M., A.W.O.) and Cell Biology and Anatomy (A.Y., A.W.O.), Louisiana State University Health Sciences Center, Shreveport; and Chemistry of Life Processes Institute, Northwestern University, Evanston, IL (A.P.M.). aorr@lsuhsc.edu.
Abstract
OBJECTIVE: Endothelial cell activation drives early atherosclerotic plaque formation. Both fibronectin deposition and accumulation of oxidized low-density lipoprotein (oxLDL) occur early during atherogenesis, and both are implicated in enhanced endothelial cell activation. However, interplay between these responses has not been established. The objective of our study was to determine whether endothelial matrix composition modulates the inflammatory properties of oxLDL. APPROACH AND RESULTS: We now show that oxLDL-induced nuclear factor-κB activation, proinflammatory gene expression, and monocyte binding are significantly enhanced when endothelial cells are attached to fibronectin compared with basement membrane proteins. This enhanced response does not result from altered oxLDL receptor expression, oxLDL uptake, or reactive oxygen species production, but results from oxLDL-induced activation of the fibronectin-binding integrin α5β1. Preventing α5β1 signaling (blocking antibodies, knockout cells) inhibits oxLDL-induced nuclear factor-κB activation and vascular cell adhesion molecule-1 expression. Furthermore, oxLDL drives α5β1-dependent integrin signaling through the focal adhesion kinase pathway, and focal adhesion kinase inhibition (PF-573228, small interfering RNA) blunts oxLDL-induced nuclear factor-κB activation, vascular cell adhesion molecule-1 expression, and monocyte adhesion. Last, treatment with the α5β1 signaling inhibitor, ATN-161, significantly blunts atherosclerotic plaque development in apolipoprotein E-deficient mice, characterized by reduced vascular cell adhesion molecule-1 expression and macrophage accumulation without affecting fibrous cap size. CONCLUSIONS: Our data suggest that α5β1-mediated cross-talk between fibronectin and oxLDL regulates inflammation in early atherogenesis and that therapeutics that inhibit α5 integrins may reduce inflammation without adversely affecting plaque structure.
OBJECTIVE: Endothelial cell activation drives early atherosclerotic plaque formation. Both fibronectin deposition and accumulation of oxidized low-density lipoprotein (oxLDL) occur early during atherogenesis, and both are implicated in enhanced endothelial cell activation. However, interplay between these responses has not been established. The objective of our study was to determine whether endothelial matrix composition modulates the inflammatory properties of oxLDL. APPROACH AND RESULTS: We now show that oxLDL-induced nuclear factor-κB activation, proinflammatory gene expression, and monocyte binding are significantly enhanced when endothelial cells are attached to fibronectin compared with basement membrane proteins. This enhanced response does not result from altered oxLDL receptor expression, oxLDL uptake, or reactive oxygen species production, but results from oxLDL-induced activation of the fibronectin-binding integrin α5β1. Preventing α5β1 signaling (blocking antibodies, knockout cells) inhibits oxLDL-induced nuclear factor-κB activation and vascular cell adhesion molecule-1 expression. Furthermore, oxLDL drives α5β1-dependent integrin signaling through the focal adhesion kinase pathway, and focal adhesion kinase inhibition (PF-573228, small interfering RNA) blunts oxLDL-induced nuclear factor-κB activation, vascular cell adhesion molecule-1 expression, and monocyte adhesion. Last, treatment with the α5β1 signaling inhibitor, ATN-161, significantly blunts atherosclerotic plaque development in apolipoproteinE-deficientmice, characterized by reduced vascular cell adhesion molecule-1 expression and macrophage accumulation without affecting fibrous cap size. CONCLUSIONS: Our data suggest that α5β1-mediated cross-talk between fibronectin and oxLDL regulates inflammation in early atherogenesis and that therapeutics that inhibit α5 integrins may reduce inflammation without adversely affecting plaque structure.
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