GRP78 upregulation by atheroprone shear stress via p38-, alpha2beta1-dependent mechanism in endothelial cells.
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.


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 alpha2beta1. 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.
Department of Biomedical Engineering, University of Virginia-Health System, PO Box 800759, Charlottesville, VA 22908, USA.
Ryan E
RE
Feaver
Nicole E
NE
Hastings
Andrew
A
Pryor
Brett R
BR
Blackman
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000502:physiology; D001783:Blood Flow Velocity / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018056:Hemorheology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology / Q000502:physiology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D048051:p38 Mitogen-Activated Protein Kinases