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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1534.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

GRP78 Upregulation by Atheroprone Shear Stress Via p38-, 2β1-Dependent Mechanism in Endothelial Cells

Ryan E. Feaver; Nicole E. Hastings; Andrew Pryor; Brett R. Blackman

From the Department of Biomedical Engineering, The Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville.

Correspondence to Brett R. Blackman, University of Virginia-Health System, PO Box 800759, Charlottesville, VA 22908. E-mail bblackman{at}virginia.edu

Objective— The initiation of atherosclerosis is in part dependent on the hemodynamic shear stress environment promoting a proinflammatory phenotype of the endothelium. Previous studies demonstrated increased expression of ER stress protein and unfolded protein response (UPR) regulator, GRP78, within all vascular cells in atherosclerotic lesions and its regulation in the endothelium by several atherosclerotic stressors; however, regulation of GRP78 by shear stress directly has not been established.

Method and Results— Using an in vitro model to simulate human arterial shear stress waveforms, atheroprone or atheroprotective flow was applied to human endothelial cells. GRP78 was found to be significantly upregulated (3-fold) in a sustained manner under atheroprone, but not atheroprotective flow up to 24 hours. This response was dependent on both sustained activation of p38, as well integrin 2β1. Increased GRP78 correlated with the activation of the ER stress sensing element (ERSE1) promoter by atheroprone flow as a marker of the UPR. Shear stress regulated GRP78 through increased protein stability when compared to other flow regulated proteins, such as connexin-43 and vascular cell adhesion molecule (VCAM)-1. Increased endothelial expression of GRP78 was also observed in atheroprone versus atheroprotective regions of C57BL6 mice.

Conclusions— This study supports a role of the hemodynamic environment in preferentially inducing GRP78 and the UPR in atheroprone regions, before lesion development, and suggests a potential atheroprotective (ie, prosurvival), compensatory effect in response to ER stress within atherosclerotic lesions.

ER stress marker GRP78 is associated with atherosclerosis, but its regulation by shear stress has not been established. GRP78 and activation of the ERSE promoter was found to be upregulated by atheroprone flow in a manner dependent on p38 and 2β1. This may provide a compensatory atheroprotective effect to reduce ER stress in atherosclerotic lesions.

Key Words: endothelial • GRP78 • shear stress • atherosclerosis • unfolded protein response

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