Abstract 256: Activation of Cell Surface GRP78 by Anti-GRP78 Autoantibodies Accelerates Lesion Development by Promoting Endothelial Cell Activation
Damage to the endothelium is an important contributor to the initiation and progression of atherosclerosis. GRP78 is a molecular chaperone localized to the endoplasmic reticulum (ER) in healthy cells that functions to assist in the correct folding of newly synthesized proteins and to prevent aggregation of folding intermediates. In addition, GRP78 is also present as a transmembrane protein on the surface of lesion-resident endothelial cells. Surface GRP78 is known to act as a membrane signaling receptor in cancer cells and is activated by anti-GRP78 autoantibodies isolated from the serum of cancer patients. We have demonstrated previously that high levels of anti-GRP78 autoantibodies accelerate lesion development in apoE-/- mice. However, the role of anti-GRP78 autoantibody activation of cell surface GRP78 on endothelial cells and how this contributes to atherogenesis is unknown. The objective of this study is to identify factors that mediate surface GRP78 expression on endothelial cells and to determine the mechanism by which surface GRP78 activation on endothelial cells contributes to atherogenesis. Here we demonstrate that induction of ER stress by tunicamycin increased surface GRP78 expression in cultured human aortic endothelial cells. We also show that activation of surface GRP78 on endothelial cells by anti-GRP78 autoantibodies significantly increases gene expression of the adhesion molecules ICAM-1 and VCAM-1. Pretreatment of these cells with a calcium chelator or an inhibitor of NF-B activation attenuated the anti-GRP78 autoantibody-induced promotion of ICAM-1 and VCAM-1. Our results suggest that signaling through cell surface GRP78 can activate intracellular pathways that contribute to endothelial cell activation, an important initiating event in atherogenesis. These findings further our understanding of the role of anti-GRP78 autoantibodies and the activation of surface GRP78 in endothelial cell function and lesion development. Furthermore, inhibiting the interaction of anti-GRP78 autoantibodies with surface GRP78 could present a novel therapeutic strategy to modulate lesion growth and thereby reduce the risk for atherosclerosis and cardiovascular disease.
Author Disclosures: E.D. Crane: None. R.C. Austin: None.
- © 2014 by American Heart Association, Inc.