Preeclampsia and pregestational diabetes are both associated with oxidative stress in the placenta which may lead to alterations in vascular function in the fetal-placental circulation and with altered trophoblast function. Both the syncytiotrophoblast and the vascular endothelium are sites of nitric oxide (NO) synthesis. The superoxide anion may regulate the bioactivity of NO as superoxide scavenges NO. The interaction of NO and superoxide however produces a relatively long-lived potent pro-oxidant the peroxynitrite anion which is highly toxic, being able to inhibit mitochondrial electron transport, oxidize protein sulphydryls groups, initiate lipid peroxidation and nitrate tyrosine residues on proteins, thus inhibiting signal transduction pathways. Peroxynitrite will damage the vasculature altering reactivity and may give rise to vascular dysfunction. Protein nitration may be a physiologic regulatory mechanism that may affect protein function or prevent further phosphorylation. Previously we have shown nitrotyrosine residues in the vascular endothelium and villous stroma of placentae from pregnancies complicated by preeclampsia or pregestational diabetes. Treatment of the placental vasculature in vitro with authentic peroxynitrite altered vascular reactivity, blunting responses to both vasoconstrictors and vasodilators, a finding similar to that in pregnancies complicated by preeclampsia or pregestational diabetes suggesting that peroxynitrite in vivo damages the fetal-placental vasculature. Using a proteomics approach we have found, with 2D gel electrophoresis and immunoprecipitation, that phospho p38 MAP kinase appears to be nitrated in the placenta and greater nitration is found in the preeclamptic placenta. Using functional assays we have shown that nitration appears to inhibit p38 MAP kinase catalytic activity. In addition we have identified p53 and PARP as nitrated proteins in these placentae. Using in vitro perfusion, cell culture and proteomic approaches we will test the overall hypothesis that generation of oxidative stress by hypoxia, hypoxia/reoxygenation or hyperglycemia leads to increased peroxynitrite synthesis and action which in turn gives increased nitration of placental proteins (specifically p38 MAP Kinase, p53 and PARP) and alters their function in the placental vascular endothelium and syncytiotrophoblast. We will use site-directed mutagenesis to identify the tyrosine residues that are nitrated in p38 MAP kinase and the functional significance of this. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075297-02
Application #
6848751
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Barouch, Winifred
Project Start
2004-02-01
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$307,000
Indirect Cost
Name
University of Cincinnati
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Evans, LaShauna; Myatt, Leslie (2017) Sexual dimorphism in the effect of maternal obesity on antioxidant defense mechanisms in the human placenta. Placenta 51:64-69
Muralimanoharan, S; Guo, C; Myatt, L et al. (2015) Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity. Int J Obes (Lond) 39:1274-81
Mele, James; Muralimanoharan, Sribalasubashini; Maloyan, Alina et al. (2014) Impaired mitochondrial function in human placenta with increased maternal adiposity. Am J Physiol Endocrinol Metab 307:E419-25
Muralimanoharan, S; Maloyan, A; Myatt, L (2013) Evidence of sexual dimorphism in the placental function with severe preeclampsia. Placenta 34:1183-9
Maloyan, A; Mele, J; Muralimanohara, B et al. (2012) Measurement of mitochondrial respiration in trophoblast culture. Placenta 33:456-8
Muralimanoharan, S; Maloyan, A; Mele, J et al. (2012) MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. Placenta 33:816-23
Myatt, L (2010) Review: Reactive oxygen and nitrogen species and functional adaptation of the placenta. Placenta 31 Suppl:S66-9
Roberts, V H J; Smith, J; McLea, S A et al. (2009) Effect of increasing maternal body mass index on oxidative and nitrative stress in the human placenta. Placenta 30:169-75
Chang, Baojun; Myatt, Leslie; Cui, Xiao-Lan (2009) Loss of proliferative capacity in a retroviral immortalized human uterine smooth muscle cell line derived from leiomyoma is restored by hTERT overexpression. Reprod Sci 16:1062-71
Webster, R P; Roberts, V H J; Myatt, L (2008) Protein nitration in placenta - functional significance. Placenta 29:985-94

Showing the most recent 10 out of 12 publications