| First Author | Chen J | Year | 2015 |
| Journal | Am J Pathol | Volume | 185 |
| Issue | 9 | Pages | 2575-89 |
| PubMed ID | 26212910 | Mgi Jnum | J:226518 |
| Mgi Id | MGI:5697618 | Doi | 10.1016/j.ajpath.2015.05.013 |
| Citation | Chen J, et al. (2015) alphavbeta3 Integrins Mediate Flow-Induced NF-kappaB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation. Am J Pathol 185(9):2575-89 |
| abstractText | 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 alpha5beta1, alphavbeta3, and alphavbeta5. 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 alphavbeta3 integrins (S247, siRNA), but not alpha5beta1 or alphavbeta5, blunts shear stress-induced proinflammatory signaling (NF-kappaB, p21-activated kinase) and gene expression (ICAM1, VCAM1). Importantly, inhibiting alphavbeta3 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 alphav integrins (S247), but not alpha5 (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 alphav integrin deletion similarly blunted inflammation in models of disturbed flow and diet-induced atherogenesis but did not affect smooth muscle incorporation. Our studies identify alphavbeta3 as the primary integrin heterodimer mediating shear stress-induced proinflammatory responses and as a key contributor to early atherogenic inflammation. |
