Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia

Abstract

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.

The role of urinary soluble endoglin in the diagnosis of pre‐eclampsia: comparison with soluble fms‐like tyrosine kinase 1 to placental growth factor ratio

“…6,8 Powerful analytical strategies as part of the novel 'discovery sciences' (genomics and proteomics) have provided opportunities for a better understanding of the pathogenesis of PE and the identification of serum and urinary protein biomarkers with diagnostic and predictive value for this disease. [8][9][10][11] Using microarray technology, it has been demonstrated recently that placental and serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and endoglin are altered in women with PE. 9,12,13 Human endoglin, also called CD105, is a dimeric membrane glycoprotein expressed at high levels on vascular endothelial cells, and functions as an anti-angiogenic factor by binding transforming growth factor b-1 (TGFb-1) and TGFb-3 proteins.…”

miR-210 Targets Iron-Sulfur Cluster Scaffold Homologue in Human Trophoblast Cell Lines

“…With proven ferroxidatic activity of this iron-transport protein, it was proposed that up-regulation of ceruloplasmin is a protective mechanism of the placenta against oxidative damage. 64 Entman et al 65,66 reported elevated serum iron in preeclamptic patients, which they attributed to increased red blood cell turnover. Furthermore, serum levels of lipid peroxides, iron, and ceruloplasmin in severe preeclampsia are elevated, whereas the transferrin level was decreased; ischemic placental tissue was proposed to be a primary source of toxic iron in preeclampsia.…”

The placenta: the forgotten essential organ of iron transport

“…70 Immunohistochemical staining in human placenta demonstrated ceruloplasmin in syncytiotrophoblasts 71,72 and fetal capillaries 71 ; however, whether the former is due to local production is uncertain, since ceruloplasmin gene (Cp) mRNA is largely restricted to the liver, retina, and endothelial cells, although mRNA expression has been detected in cultured human syncytiotrophoblasts. 71 Cp-null animals exhibit a normal phenotype at birth, suggesting that Cp is not essential for placental iron transport. 70 On the basis of the phenotype of sex-linked anemia (sla) mice that carry a mutation, the membrane-bound Cp homolog Heph appears to be important for iron egress from enterocytes.…”