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Query: UNIPROT:P06889 (Mol)
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Term human fetal membranes express prorenin, a key enzyme within the renin-angiotensin system. High levels of another vasoactive peptide, endothelin-1 (ET-1), are found in human amniotic fluid. To address the question of the relationship between these two vasoactive systems, we analyzed the expression of the components of the ET-1 system in fetal membranes in which cell types had been identified using different markers. Immunohistochemistry was performed with antibodies raised against the human proteins of the ET system. Term fetal membranes displayed ubiquitous labeling of endothelin-converting enzyme-1 (ECE-1) and ET-1. ETA receptors were detected in the chorionic connective tissue and the attached decidua; ETB receptors were localized to chorionic trophoblast cells and decidua. The localization of the ET-1 receptor subtype was confirmed by in-situ receptor binding. Renin immunoreactivity was detected in the chorionic connective tissue and the decidua. These findings suggest that ET-1 is produced ubiquitously in human fetal membranes, and its targets may be, trophoblast cells following ETB receptor activation, vascular structures and fibroblasts in the connective tissue and decidua via ETA and ETB receptors. It appears possible that renin and ET may contribute to the pathophysiological changes associated with premature labor and preeclampsia.
Cell Mol Biol (Noisy-le-grand) 2005 Dec 12
PMID:The endothelin system and renin in human fetal membranes. 1637 20

Microarray studies generating lists of genes with altered expression in placentas from pregnancies complicated with pre-eclampsia (PE) have so far been published in several different studies. Working under the assumption that altered gene expression in PE may be the result of altered expression of regulatory transcription factors (TFs), we looked for over-represented TF-binding sites (TFBSs)-which indicate the involvement of TFs in gene regulatory networks-in lists of genes (n = 143) compiled in these studies. We compared the prevalence of TFBSs in the promoter regions of 68 genes with the background prevalence of TFBSs in promoters of the human genome. The prevalence of the E47, sterol regulatory element binding protein (SREBP) and NFKB-p50 TFBSs was higher (P < 0.005) in the promoter sequences of the PE gene lists than in the background model. Each of these TFBSs could be implicated in the development of PE. The E47 protein is an E-protein or basic helix-loop-helix (bHLH) TF. Data support the role of bHLHs in the differentiation of placental tissue. SREBP-1, a lipid-sensing sterol regulatory element-binding protein, is a critical regulator of fatty acid homeostasis in the placenta. The target genes of NFKB-p50 determine inflammatory response, and aberrant cytokine homeostasis is a further sign of PE. These TFs may provide an insight into the pathogenesis of the disease.
Mol Hum Reprod 2006 Jan
PMID:Three mechanisms in the pathogenesis of pre-eclampsia suggested by over-represented transcription factor-binding sites detected with comparative promoter analysis. 1640

Preeclampsia is a pregnancy-specific disorder characterised by hypertension and proteinuria occurring after the 20th week of gestation. Delivery of the placenta results in resolution of the condition, implicating the placenta as a central culprit in the pathogenesis of preeclampsia. In preeclampsia, an inadequate placental trophoblast invasion of the maternal uterine spiral arteries results in poor placental perfusion, leading to placental ischaemia. This could result in release of factors into the maternal circulation that cause widespread activation or dysfunction of the maternal endothelium. Factors in the maternal circulation might induce oxidative stress and/or elicit an inflammatory response in the maternal endothelium, resulting in the altered expression of several genes involved in the regulation of vascular tone. This review addresses the potential circulating factors and the molecular mechanisms involved in the alteration of vascular function that occurs in preeclampsia.
Expert Rev Mol Med 2006 Jan 26
PMID:Preeclampsia: current understanding of the molecular basis of vascular dysfunction. 1643 53

The typically lysosomal family of cysteine cathepsin proteases has been implicated in the development of the placenta in particular, from studies in the mouse. Here, we analysed overall expression, regulation and presence of transcript isoforms of cysteine cathepsins during human extra-embryonic development. All 11 family members are expressed in human placental tissues, and many are differentially regulated during gestation. Several cysteine cathepsins exhibit deregulated expression levels in placentas from pregnancies complicated by pre-eclampsia. The localization of cathepsin B predominantly in placental and decidual macrophages suggests a role in the physiological functions of these cells in mediating villous angiogenesis and decidual apoptosis. Cathepsin L levels are highest in a subpopulation of invasive cytotrophoblasts. Reflecting the expression pattern of two murine cathepsins, these data give insights into the evolutionary conservation of cathepsin function that is not necessarily exhibited by gene pairs defined by highest sequence similarity. Furthermore, cathepsin L protein localization in uterine epithelial cells demonstrates the in vivo occurrence of intranuclear cathepsin L isoforms. The zonally restricted expression of cathepsin in the syncytiotrophoblast may be important for the metabolic breakdown of maternal nutrients. Overall, the distribution and abnormal expression levels in pre-eclamptic placentas indicate that cysteine cathepsins may play important roles during normal placentation and in the etiology of pre-eclampsia.
J Mol Med (Berl) 2006 Apr
PMID:The importance of cysteine cathepsin proteases for placental development. 1655 97

Although many candidate genes have been studied in pre-eclampsia (PE), the important class of catecholamine receptors that contribute to sympathetic tone and blood pressure regulation has yet to be investigated. We therefore examined the dopamine D4 receptor (DRD4) gene. We performed a prospective family-based study in 50 families (patient and both her parents) who were genotyped for three DRD4 promoter regions. These single-nucleotide polymorphisms (SNPs) were tested for association using family-based association test (FBAT) that also included two quantitative measures, aspartate aminotransferase [serum glutamic oxalacetic transaminase (SGOT)] and systolic blood pressure. SNPs were assayed using a commercially available SNAPSHOT kit and PCR products were analysed in an ABI 310 DNA analyser. A significant association (preferential transmission of the T allele from a heterozygous parent to affected mother) was observed between the -C521T SNP and PE (P = 0.019). Significant association was also observed between the -521T allele and two-dimensional measures of PE : GOT (P = 0.039) and systolic blood pressure (P = 0.036). The DRD4 promoter region -C521T SNP that reduces transcriptional efficiency of this gene is suggested to contribute to developing PE. Additionally, DRD4 -521 TT homozygosity may be a marker for severe PE.
Mol Hum Reprod 2006 Feb
PMID:Association between a functional dopamine D4 receptor promoter region polymorphism (-C521T) and pre-eclampsia: a family-based study. 1645 20

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are unknown. The initiating event in preeclampsia has been postulated to be reduced uteroplacental perfusion. Placental ischemia/hypoxia is thought to lead to widespread activation/dysfunction of the maternal vascular endothelium, vasoconstriction and hypertension. Experimental induction of chronic uteroplacental ischemia appears to be the most promising animal model to study potential mechanisms of preeclampsia since reductions in uteroplacental blood flow in a variety of animal models lead to a hypertensive state that closely resembles preeclampsia in women. This chapter details the methods we use in our laboratory to produce the reduced uterine perfusion pressure (RUPP) model in the pregnant rat.
Methods Mol Med 2006
PMID:Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia. 1651 95

Preeclampsia is characterized by the clinical triad of new hypertension, proteinuria, and edema after 20 wk of gestation. Recent evidence suggests that disturbances in angiogenic factors (such as vascular endothelial growth factor and placental growth factor) signaling and endothelial health may play a major role in the pathogenesis of preeclampsia. Exogenous administration of soluble fms-like tyrosine kinase-1 (sFlt-1; a circulating anti-angiogenic protein) results in a preeclampsia-like phenotype in rats. This chapter describes the methods we use in our laboratory to create the sFlt-1 induced-rat model of preeclampsia.
Methods Mol Med 2006
PMID:In vivo rat model of preeclampsia. 1651 96

Immunological imbalances have been hypothesized as a cause for the onset of preeclampsia, which is a very severe, pregnancy-related disease. We recently described a novel preeclampsia mouse model by adoptively transferring activated BALB/c Th1-like splenocytes into allogeneically pregnant BALB/c female mice during late gestation. This cell transfer provoked preeclampsia symptoms (increased blood pressure and glomerulonephritis accompanied by proteinuria). Interestingly, preeclampsia-like symptoms could not be detected in nonpregnant animals receiving activated Th1-like cells. Adoptive cell transfer further affected pregnancy outcome by increasing fetal rejection through an inflammatory profile of uterine immune cells. This chapter describes the methods employed to develop the model as well as additional experiments developed to analyze cellular and molecular mechanisms involved.
Methods Mol Med 2006
PMID:A novel mouse model for preeclampsia by transferring activated th1 cells into normal pregnant mice. 1651 97

Oxygen has a profound influence on the behavior of many cell types, including trophoblast. The effects are mediated in part through the generation of oxygen free radicals, which act as signaling molecules. Because of their high reactivity, free radicals are, however, potentially damaging to a wide range of biomolecules, and if concentrations exceed homeostatic levels then cellular oxidative stress results. Responses of tissues to changes in oxygen concentration may therefore range from physiological adaptations to pathological insults. Placental development is heavily modulated by the prevailing oxygen concentration, and understanding the mechanisms involved is clearly important. Equally, trophoblastic oxidative stress plays a key role in the pathogenesis of pregnancy complications such as miscarriage and preeclampsia. This chapter describes techniques by which the effects of oxygen and oxidative stress on placental tissues can be systematically investigated in vitro.
Methods Mol Med 2006
PMID:Working with oxygen and oxidative stress in vitro. 1651 98

The relationship between Pre-eclampsia (PE) and placental production of Adrenomedullin (AdM) is not completely understood. This study measured placental and fetal membrane AdM protein concentrations by specific radioimmunoassay and mRNA expression by Northern blot analysis in samples obtained at either term or preterm gestation from women either in labour or not in labour. Samples were obtained from women with normotensive and pre-eclamptic pregnancies. There were significant increases in immunoreactive AdM protein concentration (pg/mg DNA) in choriodecidua and amnion of women with PE compared to normal pregnancy for the preterm not-in-labour group (choriodecidua: control 124 +/- 16, n = 10, PE 361 +/- 35, n = 10; amnion: control 94 +/- 12, n = 10, PE 153 +/- 19, n = 10) and for the term not-in-labour (choriodecidua: control 128 +/- 17, n = 14, PE 459 +/- 51, n = 8; amnion: control 112 +/- 15, n = 14, PE 253 +/- 57, n = 8) and in-labour (choriodecidua: control 531 +/- 74, n = 14, PE 881 +/- 188, n = 8; amnion: control 545 +/- 84, n = 14, PE 1008 +/- 230, n = 8) groups. AdM mRNA relative abundance was greater in preterm, not-in-labour choriodecidual samples in PE, but not in amnion. In addition, this study observed labour-associated increases in choriodecidual and amniotic irAdM in term pre-eclamptic and control patients. However, there were no significant changes in AdM protein or mRNA expressions between any of the groups for placental tissue. These results suggest that fetal membranes, but not placental, production of AdM is increased at the post-translational level during PE in preterm and term tissues and at the pre-translational level during PE in preterm tissues. Fetal membranes, AdM may play an important role in the regulation of feto-placental hemodynamics and fetal physiology during pre-eclampsia.
Mol Hum Reprod 2006 Mar
PMID:Increased adrenomedullin protein content and mRNA expression in human fetal membranes but not placental tissue in pre-eclampsia. 1651 13


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