Epidermal Growth Factor-Like Domain 7 Is a Novel Inhibitor of Neutrophil Adhesion to Coronary Artery Endothelial Cells Injured by Calcineurin Inhibition

[摘要] Background-We investigated the effect of epidermal growth factor-like domain 7 (Egfl7) on nuclear factor-kappa B 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 mu g/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-kappa B (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-kappa B 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-kappa B pathway activation and intercellular adhesion molecule-1 expression, which suggests that it may have significant anti-inflammatory properties. Because Jagged1 blocked the effect of Egfl7, Notch receptor antagonism may contribute to the mechanism of action of Egfl7. (Circulation. 2011; 124[suppl 1]:S197-S203.)

[效力级别]  Proceedings Paper

[关键词] NF-KAPPA-B;MICROVASCULAR ENDOTHELIUM;MOLECULE-1 EXPRESSION;LEUKOCYTE ADHESION;NITRIC-OXIDE;CYCLOSPORINE;EGFL7;ICAM-1;NOTCH;MECHANISMS