Xu Dong, Perez Ricardo E, Ekekezie Ikechukwu I, Navarro Angels, Truog William E
Am J Physiol Lung Cell Mol Physiol. 2008 Jan;294(1):L17-23. doi: 10.1152/ajplung.00178.2007. Epub 2007 Oct 12.
Hyperoxia is one of the major contributors to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants. Emerging evidence suggests that the arrested lung development of BPD is associated with pulmonary endothelial cell death and vascular dysfunction resulting from hyperoxia-induced lung injury. A better understanding of the mechanism of hyperoxia-induced endothelial cell death will provide critical information for the pathogenesis and therapeutic development of BPD. Epidermal growth factor-like domain 7 (EGFL7) is a protein secreted from endothelial cells. It plays an important role in vascular tubulogenesis. In the present study, we found that Egfl7 gene expression was significantly decreased in the neonatal rat lungs after hyperoxic exposure. The Egfl7 expression was returned to near normal level 2 wk after discounting oxygen exposure during recovery period. In cultured human endothelial cells, hyperoxia also significantly reduced Egfl7 expression. These observations suggest that diminished levels of Egfl7 expression might be associated with hyperoxia-induced endothelial cell death and lung injury. When we overexpressed human Egfl7 (hEgfl7) in EA.hy926 human endothelial cell line, we found that hEgfl7 overexpression could partially block cytochrome c release from mitochondria and decrease caspase-3 activation. Further Western blotting analyses showed that hEgfl7 overexpression could reduce expression of a proapoptotic protein, Bax, and increase expression of an antiapoptotic protein, Bcl-xL. Theses findings indicate that hEGFL7 may protect endothelial cell from hyperoxia-induced apoptosis by inhibition of mitochondria-dependent apoptosis pathway.
高氧是支气管肺发育不良（BPD）发生发展的主要因素之一，BPD是一种早产儿慢性肺部疾病。新出现的证据表明，BPD中肺发育停滞与高氧诱导的肺损伤导致的肺内皮细胞死亡和血管功能障碍有关。更好地了解高氧诱导内皮细胞死亡的机制将为BPD的发病机制和治疗发展提供关键信息。表皮生长因子样结构域7（EGFL7）是一种由内皮细胞分泌的蛋白质。它在血管形成中起重要作用。在本研究中，我们发现高氧暴露后新生大鼠肺中Egfl7基因表达显著降低。在恢复期停止高氧暴露2周后，Egfl7表达恢复到接近正常水平。在培养的人内皮细胞中，高氧也显著降低了Egfl7表达。这些观察结果表明，Egfl7表达水平降低可能与高氧诱导的内皮细胞死亡和肺损伤有关。当我们在EA.hy926人内皮细胞系中过表达人Egfl7（hEgfl7）时，我们发现hEgfl7过表达可以部分阻止细胞色素c从线粒体释放并减少caspase-3激活。进一步的蛋白质印迹分析表明，hEgfl7过表达可以降低促凋亡蛋白Bax的表达并增加抗凋亡蛋白Bcl-xL的表达。这些发现表明，hEGFL7可能通过抑制线粒体依赖性凋亡途径保护内皮细胞免受高氧诱导的凋亡。
