title: αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation.
abstract: Endothelial cell interactions with transitional matrix proteins, such as fibronectin, occur early during atherogenesis and regulate shear stress-induced endothelial cell activation. Multiple endothelial cell integrins bind transitional matrix proteins, including α5β1, αvβ3, and αvβ5. However, the role these integrins play in mediating shear stress-induced endothelial cell activation remains unclear. Therefore, we sought to elucidate which integrin heterodimers mediate shear stress-induced endothelial cell activation and early atherogenesis. We now show that inhibiting αvβ3 integrins (S247, siRNA), but not α5β1 or αvβ5, blunts shear stress-induced proinflammatory signaling (NF-κB, p21-activated kinase) and gene expression (ICAM1, VCAM1). Importantly, inhibiting αvβ3 did not affect cytokine-induced proinflammatory responses or inhibit all shear stress-induced signaling, because Akt, endothelial nitric oxide synthase, and extracellular regulated kinase activation remained intact. Furthermore, inhibiting αv integrins (S247), but not α5 (ATN-161), in atherosclerosis-prone apolipoprotein E knockout mice significantly reduced vascular remodeling after acute induction of disturbed flow. S247 treatment similarly reduced early diet-induced atherosclerotic plaque formation associated with both diminished inflammation (expression of vascular cell adhesion molecule 1, plaque macrophage content) and reduced smooth muscle incorporation. Inducible, endothelial cell-specific αv integrin deletion similarly blunted inflammation in models of disturbed flow and diet-induced atherogenesis but did not affect smooth muscle incorporation. Our studies identify αvβ3 as the primary integrin heterodimer mediating shear stress-induced proinflammatory responses and as a key contributor to early atherogenic inflammation.
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Jonette
authors.initials: J
authors.lastname: Green
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana; Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Arif
authors.initials: A
authors.lastname: Yurdagul
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Patrick
authors.initials: P
authors.lastname: Albert
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana.
authors.forename: Marshall C
authors.initials: MC
authors.lastname: McInnis
authors.affiliation: Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana. Electronic address: aorr@lsuhsc.edu.
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1