Epidermal growth factor-like domain 7 protects endothelial cells from hyperoxia-induced cell death

• Published in: American journal of physiology. Lung cellular and molecular physiology 2008-01, Vol.294 (1), p.L17-L23
• Main Authors: Xu, Dong, Perez, Ricardo E, Ekekezie, Ikechukwu I, Navarro, Angels, Truog, William E
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Apoptosis; Bronchitis; Bronchopulmonary Dysplasia - prevention & control; Cell Survival - physiology; Endothelial Growth Factors - genetics; Endothelial Growth Factors - physiology; Endothelium, Vascular - physiology; Endothelium, Vascular - physiopathology; Gene expression; Gene Expression Regulation; Humans; Hyperoxia - physiopathology; Hyperoxia - prevention & control; Hypoxia; Infant, Newborn; L-Lactate Dehydrogenase - analysis; Proteins; Rats; Studies; Transfection
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00178.2007

Neonatology Research Laboratory, Neonatology Section, Department of Pediatrics, Children's Mercy Hospital, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri Submitted 2 May 2007 ; accepted in final form 11 October 2007 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. apoptosis; necrosis; lung injury; chronic lung disease Address for reprint requests and other correspondence: D. Xu, Neonatology Research Laboratory, Children's Mercy Hospital, Pediatric Research Center, 4th Floor, 2401 Gillham Rd., Kansas City, MO 64108 (e-mail: xud{at}umkc.edu )