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.
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