Atherosclerosis is thought to be initiated by endothelial cell dysfunction. Research described in this dissertation is focused on interactions of nutrients, cytokines and pharmaceutical compounds in the intracellular signaling pathways leading to endothelial cell activation. The flavonoid quercetin could significantly downregulate the inflammatory pathways induced by linoleic acid as determined by DNA binding assays of the proinflammatory transcription factors nuclear factor-kappaB and activator protein-1 as well as by gene expression studies of interleukin-6 and vascular adhesion molecule-1. Interestingly, quercetin and vitamin E also prevented the linoleic acid-induced activation of PPAR DNA binding - suggesting a role of oxidation in the fatty acid-mediated induction of PPAR. In addition, we studied an interaction of zinc with the antiinflammatory transcription factors, peroxisome proliferator activated receptors (PPARs) alpha and gamma. Our data suggest that PPAR alpha and gamma and their synthetic agonists require zinc for their antiinflammatory properties in endothelial cells. We could confirm the importance of zinc in PPAR gamma signaling in vivo by a decreased PPAR DNA binding activity in livers of zinc deficient mice. Furthermore, zinc had dramatic lipid lowering effects in LDL-receptor deficient mice on a diet rich in corn oil. Triglycerides, phospholipids and cholesterol levels were significantly elevated in mice receiving a zinc deficient diet when compared to control and where decreased in zinc supplemented animals. Zinc deficiency also increased oxidative stress as determined by quantitation of plasma isoprostanes and mRNA expression of glutathione reductase. In conclusion, our data show novel interactions of proinflammatory nutrients, such as linoleic acid, with antioxidant and anti-inflammatory nutrients, such as quercetin and zinc.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:gradschool_diss-1403 |
| Date | 01 January 2004 |
| Creators | Reiterer, Gudrun |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of Kentucky Doctoral Dissertations |
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