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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/L44    most recent 90626.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Xu, D. Articles by Truog, W. E. PubMed PubMed Citation Articles by Xu, D. Articles by Truog, W. E.

Knockdown of ERp57 increases BiP/GRP78 induction and protects against hyperoxia and tunicamycin-induced apoptosis

¹Neonatology Research Laboratory, Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri; and ²Molecular and Cellular Toxicology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Submitted 16 December 2008 ; accepted in final form 24 April 2009

Supplemental oxygen therapy (hyperoxia) in preterm babies with respiratory stress is associated with lung injury and the development of bronchopulmonary dysplasia. Endoplasmic reticulum (ER) homeostasis plays critical roles in maintaining cellular functions such as protein synthesis, folding, and secretion. Interruption of ER homeostasis causes ER stress and triggers the unfolded protein response, which can lead to apoptosis in persistently stressed cells. ERp57 is an ER protein and is associated with calreticulin and calnexin in protein glycosylation. In this study, we found hyperoxia downregulated ERp57 in neonatal rat lungs and cultured human endothelial cells. Transient transfection of ERp57 small interfering RNA significantly knocked down ERp57 expression and reduced hyperoxia- or tunicamycin-induced apoptosis in human endothelial cells. Apoptosis was decreased from 26.8 to 9.9% in hyperoxia-exposed cells and from 37.8 to 5.0% in tunicamycin-treated cells. The activation of caspase-3 induced by hyperoxia or tunicamycin was diminished and immunoglobulin heavy chain-binding protein/glucose-regulated protein 78-kDa (BiP/GRP78) induction was increased in ERp57 knockdown cells. Overexpression of ERp57 exacerbated hyperoxia- or tunicamycin-induced apoptosis in human endothelial cells. Apoptosis was increased from 10.1 to 14.3% in hyperoxia-exposed cells and from 14.0 to 21.2% in tunicamycin-treated cells. Overexpression of ERp57 also augmented tunicamycin-induced caspase-3 activation and reduced BiP/GRP78 induction. Our results demonstrate that ERp57 can regulate apoptosis in human endothelial cells. It appears that knockdown of ERp57 confers cellular protection against hyperoxia- or tunicamycin-induced apoptosis by inhibition of caspase-3 activation and stimulation of BiP/GRP78 induction.

endoplasmic reticulum stress; unfolded protein response; lung injury; bronchopulmonary dysplasia; immunoglobulin heavy chain-binding protein