Document Detail

Epidermal growth factor-like domain 7 is a novel inhibitor of neutrophil adhesion to coronary artery endothelial cells injured by calcineurin inhibition.
MedLine Citation:
PMID:  21911813     Owner:  NLM     Status:  In-Data-Review    
Background- We investigated the effect of epidermal growth factor-like domain 7 (Egfl7) on nuclear factor-κB activation, intercellular adhesion molecule-1 expression, and neutrophil adhesion to human coronary artery endothelial cells after calcineurin-inhibition-induced injury. Methods and Results- Human coronary endothelial cells were incubated with cyclosporine (CyA) 10 μg/mL with or without Egfl7 (100 ng/mL) or the Notch receptor activator Jagged1 (200 ng/mL) for 6 to 48 hours. CyA upregulated nuclear factor-κB (p65) activity (128±2% of control, P<0.001) in nuclear extracts, as determined with a DNA-binding activity ELISA. This activity was inhibited by Egfl7 (86±3% of control; P<0.001 versus CyA alone). Jagged1 blocked Egfl7-induced nuclear factor-κB inhibition (105±4% of control; P<0.05 versus CyA plus Egfl7). CyA upregulated cell-surface intercellular adhesion molecule-1 expression (215±13% of control; P<0.001), as determined by flow cytometry. This expression was suppressed by Egfl7 (148±5%; P<0.001 versus CyA alone). Jagged1 attenuated the intercellular adhesion molecule-1-suppressive effect of Egfl7 when administered with CyA (193±3% versus 148±5%; P<0.01). CyA increased neutrophil adhesion to human coronary endothelial cells (control 20±5%, CyA 37±3%; P<0.001 versus control) in a nonstatic neutrophil adhesion assay. This increase was attenuated by Egfl7 (22±6%; P<0.001 versus CyA alone). Jagged 1 attenuated the effect of Egfl7 on neutrophil adhesion (31±3%; P<0.001 versus Egfl7 plus CyA). Conclusions- Our study reveals that Egfl7 is a potent inhibitor of neutrophil adhesion to human coronary endothelial cells subsequent to calcineurin-inhibition-induced injury. Mechanistically, Egfl7 blocked nuclear factor-κB pathway activation and intercellular adhesion molecule-1 expression, which suggests that it may have significant antiinflammatory properties. Because Jagged1 blocked the effect of Egfl7, Notch receptor antagonism may contribute to the mechanism of action of Egfl7.
Mitesh V Badiwala; Daipayan Guha; Laura Tumiati; Jemy Joseph; Arash Ghashghai; Heather J Ross; Diego H Delgado; Vivek Rao
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Circulation     Volume:  124     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S197-203     Citation Subset:  AIM; IM    
Professor of Surgery, Alfredo and Teresa DeGasperis Chair in Heart Failure Surgery, Division of Cardiovascular Surgery, Toronto General Hospital, University of Toronto, 4N-464, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada.
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