Protein disulfide isomerase (PDI AI or PDI) is an important chaperone that acts in the oxidative folding in the endoplasmic reticulum with emerging role in signaling and redox homeostasis pathways, including NADPH oxidases interaction. A specific pool PDI presents in the extracellular space of several cell types and regulates processes like thrombosis, cell adhesion, viral infection and vascular remodeling. This pool, denominate PDI epi/pericelullar (pecPDI), modulates thiol redox reactions thats regulates: integrins, thrombospondin, metalloproteases, galectin 9, glycoprotein gp120 of HIV virus and tissue factor. The interaction between pecPDI and integrins (an important mecanosensor) and redox role of pecPDI suggest a possible modulation by pecPDI of shear stress responses in endothelial cells. Our group investigated PDI externalization and recently identify a pathway Golgi independent involving GRASP, a newly described protein as unconventional secretion pathway. Our hypothesis is that in response to shear stress in endothelial cells, the pecPDI is externalized by GRASP pathway and, in addition with others potential actions of GRASP, acts like integrate mechanism of mechanotransduction. We investigate the effect of GRASP-pecPDI pathway on activation of integrins and cytoskeleton organization, like associate subcellular mechanisms, in response to laminar shear stress in endothelial cells. In this way, we evaluate, in response to laminar shear stress: kinetics of PDI externalization, proteins that interact with PDI on the cell surface, PDI effects on the integrins activation, redox state changes of integrins and PDI, effects of gain loss function GRASP55/65 and GRASP phosphorylation of GRASP. These data must contribute to integrate understanding of mechanotransduction pathway in endothelial cells, provide conceptual advances and physiopathological implications.
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