&agr;5&bgr;1 Integrin Signaling Mediates Oxidized Low-Density Lipoprotein–Induced Inflammation and Early Atherosclerosis

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-&kgr;B 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 &agr;5&bgr;1. Preventing &agr;5&bgr;1 signaling (blocking antibodies, knockout cells) inhibits oxLDL-induced nuclear factor-&kgr;B activation and vascular cell adhesion molecule-1 expression. Furthermore, oxLDL drives &agr;5&bgr;1-dependent integrin signaling through the focal adhesion kinase pathway, and focal adhesion kinase inhibition (PF-573228, small interfering RNA) blunts oxLDL-induced nuclear factor-&kgr;B activation, vascular cell adhesion molecule-1 expression, and monocyte adhesion. Last, treatment with the &agr;5&bgr;1 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 &agr;5&bgr;1-mediated cross-talk between fibronectin and oxLDL regulates inflammation in early atherogenesis and that therapeutics that inhibit &agr;5 integrins may reduce inflammation without adversely affecting plaque structure.

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