PT  - JOURNAL ARTICLE
AU  - Konstantin Birukov
AU  - Patrick Singleton
AU  - Tamara Mirzapoiazova
AU  - Tinghuai Wu
TI  - GRP78 is a novel receptor initiating endothelial barrier protective response to oxidized phospholipids
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - 3426
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/3426.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/3426.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - Vascular integrity or the maintenance of blood vessel continuity is a fundamental process maintained through endothelial cell-cell junctions. Defects in endothelial barrier function are an initiating factor in several disease processes including atherosclerosis, ischemia/reperfusion, tumor angiogenesis, cancer metastasis, diabetes, sepsis and acute lung injury. Therefore, understanding the mechanisms of endothelial barrier enhancement can provide novel therapeutic strategies. We have previously reported that oxidized phospholipids promote endothelial cell (EC) barrier enhancement both in vitro and in vivo. In this study, we examined the initiating mechanistic events triggered by oxidized phospholipids (OxPAPC) to increase vascular integrity. Our novel data indicate that OxPAPC directly binds to the cell membrane localized chaperone protein, GRP78, associated with its cofactor, HTJ1. We found that plasma membrane localization of GRP78 is essential for trafficking of the barrier protective sphingosine 1-phosphate receptor 1 (S1P-R1) to caveolin-enriched microdomains (CEM) and consequent activation of S1P-R1, Src and Fyn tyrosine kinases and recruitment of Rac1 to CEM, processes essential for actin cytoskeletal reorganization and EC barrier enhancement. Using an animal model of acute lung injury with vascular hyper-permeability, we observed that vascular silencing of HTJ blocked OxPAPC protection from ventilator-induced lung injury and vascular leak. Our data demonstrate an essential role of GRP78 and HTJ as a bona fide receptor complex triggering the OxPAPC-mediated CEM dynamics and enhancement of vascular integrity.Sources of funding: HL076259, HL087823.