Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia

• Published in: Laboratory investigation Vol. 88; no. 10; pp. 1057 - 1067
• Main Authors: Guller, Seth, Buhimschi, Catalin S, Ma, Yula Y, Huang, Se Te J, Yang, Liubin, Kuczynski, Edward, Zambrano, Eduardo, Lockwood, Charles J, Buhimschi, Irina A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2008; Nature Publishing; Nature Publishing Group
• Subjects: Adult; Biological and medical sciences; Biotechnology; Case-Control Studies; Cells, Cultured; Ceruloplasmin - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Humans; Hypoxia - physiopathology; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Medical sciences; Medicine; Medicine & Public Health; Oligonucleotide Array Sequence Analysis; Pathology; Placenta - metabolism; Pre-Eclampsia - metabolism; Pre-Eclampsia - physiopathology; Pregnancy; Premature Birth - metabolism; research-article; RNA, Messenger - metabolism; Trophoblasts - metabolism; Up-Regulation; ceruloplasmin; hypoxia; placenta; preeclampsia; oxygen radicals; Ceruloplasmin; Biotechnology; Ferroxidase; Oxygen; Pregnancy disorders; Fetal membrane; Enzyme; Pregnancy toxemia; Free radical; Pregnancy; Placenta; Preeclampsia; Clinical biology; Complication; Female; Hypoxia; Oxidoreductases; Severe
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2008.74

There is consensus that ischemia/reperfusion injury associated with preeclampsia (PE) promotes both placental damage and the release of factors leading to maternal endothelium dysfunction, a hallmark of this potentially life-threatening syndrome. These factors include plasminogen activator inhibitor-1 (PAI-1) and soluble fms-like tyrosine kinase-1 (sFlt-1). The goal of this study was to further characterize placental factors involved in the pathophysiology of PE. Thus, DNA microarray gene profiling was utilized to identify mRNA differentially regulated in placentas from women with severe PE compared to both preterm (PC) and term control (TC) groups. Microarray studies detected an upregulation of mRNA for ceruloplasmin, a copper-containing iron transport protein with antioxidant ferroxidase properties, in PE compared to PC and TC placentas, respectively. Quantitative real-time PCR confirmed these results by demonstrating significant increases in ceruloplasmin mRNA in PE vs PC and TC placentas. Supporting previous reports, the expression of sFlt-1 and PAI-1 were also upregulated in PE placentas. Immunohistochemistry localized ceruloplasmin to the intervillous space in PE and PC placentas, whereas stronger syncytial staining was noted in PE. Western blotting confirmed a significant increase in ceruloplasmin levels in placental tissue in PE compared to PC groups. PCR identified the presence of mRNA for ceruloplasmin in primary cultures of syncytiotrophoblasts, but not villous-derived fibroblasts, suggesting that syncytium is the site of ceruloplasmin synthesis in placenta. Hypoxic treatment (1% O 2 ) of syncytiotrophoblasts enhanced levels of ceruloplasmin mRNA approximately 25-fold, a significantly greater upregulation than that noted for PAI-1 and sFlt-1, suggesting that enhanced ceruloplasmin expression is a sensitive marker of syncytial hypoxia. We suggest that syncytial ceruloplasmin and its associated ferroxidase activity, induced by the hypoxia accompanying severe PE, is important in an endogenous cellular program to mitigate the damaging effects of subsequent reperfusion injury at this site.