The central hypothesis is that during preeclampsia increased free fatty acids bound by albumin and/or modification of Cys34 impair normal albumin/copper interactions in such a way that 'loosely-bound"""""""" copper is capable of catalyzing redox cycling resulting in the generation of reactive oxygen species. The first goal is to establish that changes in copper/albumin interactions can trigger copper-dependent redox cycling and oxidative stress in preeclampsia. Using plasma obtained from preeclamptic and normal pregnant women, the investigator will 1) establish that preeclamptic plasma contains enhanced potential for generating copper-dependent oxidative stress and 2) determine the role for free fatty acids and thiol oxidation/nitrosylation of albumin in mediating this enhancement. The second goal is to use a simple model system utilizing purified human serum albumin to define the molecular mechanisms for free fatty acid and Cys34 modification of copper/albumin interactions and redox cycling. The third goal is to determine whether enhanced redox cycling of copper/albumin can alter the vascular behavior by: 1) demonstrating the potential of preeclamptic plasma to alter vascular function in mesenteric arteries from pregnant mice, and 2) establishing that free fatty acid and Cys34, modification of albumin can result in copper-dependent alterations in vascular reactivity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064145-02
Application #
6390598
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Barouch, Winifred
Project Start
2000-09-15
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$282,362
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Bayir, Hulya; Kagan, Valerian E; Clark, Robert S B et al. (2007) Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury. J Neurochem 101:168-81
Gandley, Robin E; Tyurin, Vladimir A; Huang, Wan et al. (2005) S-nitrosoalbumin-mediated relaxation is enhanced by ascorbate and copper: effects in pregnancy and preeclampsia plasma. Hypertension 45:21-7
Bayir, Hulya; Kagan, Valerian E; Borisenko, Grigory G et al. (2005) Enhanced oxidative stress in iNOS-deficient mice after traumatic brain injury: support for a neuroprotective role of iNOS. J Cereb Blood Flow Metab 25:673-84
Stoyanovsky, Detcho A; Tyurina, Yulia Y; Tyurin, Vladimir A et al. (2005) Thioredoxin and lipoic acid catalyze the denitrosation of low molecular weight and protein S-nitrosothiols. J Am Chem Soc 127:15815-23
Heck, Diane E; Kagan, Valerian E; Shvedova, Anna A et al. (2005) An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis. Toxicology 208:259-71
Borisenko, Grigory G; Martin, Ian; Zhao, Qing et al. (2004) Nitroxides scavenge myeloperoxidase-catalyzed thiyl radicals in model systems and in cells. J Am Chem Soc 126:9221-32
Borisenko, Grigory G; Martin, Ian; Zhao, Qing et al. (2004) Glutathione propagates oxidative stress triggered by myeloperoxidase in HL-60 cells. Evidence for glutathionyl radical-induced peroxidation of phospholipids and cytotoxicity. J Biol Chem 279:23453-62
Taylor, R N; de Groot, C J M (2004) Pre-eclampsia and vascular activation in women and non-human primates. Gynecol Obstet Invest 57:38-40
Serinkan, Behice F; Tyurina, Yulia Y; Babu, Hareesh et al. (2004) Vitamin E inhibits anti-Fas-induced phosphatidylserine oxidation but does not affect its externalization during apoptosis in Jurkat T cells and their phagocytosis by J774A.1 macrophages. Antioxid Redox Signal 6:227-36
Kagan, V E; Kuzmenko, A I; Shvedova, A A et al. (2003) Direct evidence for recycling of myeloperoxidase-catalyzed phenoxyl radicals of a vitamin E homologue, 2,2,5,7,8-pentamethyl-6-hydroxy chromane, by ascorbate/dihydrolipoate in living HL-60 cells. Biochim Biophys Acta 1620:72-84

Showing the most recent 10 out of 33 publications