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

DOI：

10.1161/circulationaha.110.011734

发表时间：

2011-09-13

期刊：

CIRCULATION

影响因子：

37.8

通讯作者：

中科院分区：

医学1区

文献类型：

--

作者：

Badiwala, Mitesh V.;Guha, Daipayan;Rao, Vivek

背景-我们研究了在钙调神经磷酸酶抑制诱导的损伤后，表皮生长因子样域7(Egfl7)对人冠状动脉内皮细胞核因子-kappaB活化、细胞间黏附分子-1表达以及中性粒细胞与人冠状动脉内皮细胞黏附的影响。方法与结果：人冠状动脉内皮细胞与环孢素A(CyA)10 mU g/m l加或不加Egfl7(100 ng/m L)或Notch受体激活剂Jagged1(200 ng/m L)孵育6~48小时。用DNA结合活性ELISA法测定，CyA可上调细胞核提取液中核因子-kappaB(P65)活性(为对照的128%+/-2%，P&lt；0.001)。这种活性被Egfl7抑制(对照组的86%+/-3%；P&lt；0.001比CyA单独抑制)。Jagged1阻断Egfl7诱导的核因子-kappa B抑制(对照的105+/-4%；P&lt；0.05与CyA+Egfl7相比)。流式细胞仪检测，CyA上调细胞表面细胞间黏附分子-1的表达(为对照组的215%+/-13%；P&lt；0.001)。这种表达被Egfl7抑制(148+/-5%；P&lt；0.001与CyA单独作用相比)。当给予CyA时，Jagged1可减弱Egfl7对细胞间黏附分子-1的抑制作用(193+/-3%比148+/-5%；P&lt；0.01)。在非静态中性粒细胞黏附实验中，CyA增加了中性粒细胞与人冠状动脉内皮细胞的黏附(对照组为20+/-5%，CyA为37+/-3%；P&lt；0.001与对照组相比)。这种增加被Egfl7减弱(22+/-6%；P&lt；0.001与CyA单独相比)。锯齿状1可减弱Egfl7对中性粒细胞黏附的影响(31+/-3%；P&lt；0.001 vs Egfl7+CyA)。结论：我们的研究显示Egfl7是钙调神经磷酸酶抑制损伤后中性粒细胞与人冠状动脉内皮细胞黏附的有效抑制物。Egfl7在机制上阻断了核因子-kappaB途径的激活和细胞间黏附分子-1的表达，提示其可能具有显著的抗炎作用。由于Jagged1阻断了Egfl7的作用，Notch受体拮抗作用可能参与了Egfl7的作用机制。(发行量。2011；124[附录1]：S197-S203。)

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.)