Graduate Thesis Or Dissertation
 

Underlying Mechanisms of the Anti-inflammatory and Antioxidant Effects of Quercetin in Human Aortic Endothelial Cells : Implications for Vascular Inflammation and Atherosclerosis

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/j3860c39w

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  • Atherosclerosis is the underlying cause of ischemic heart disease and stroke and is the leading cause of death worldwide, especially in developed countries. As an inflammatory disease of arteries in a hyperlipidemic milieu, expression of adhesion molecules, such as endothelial-leukocyte adhesion molecule-1 (E-selectin) and intercellular adhesion molecule-1 (ICAM-1), on endothelial cell surfaces is critical for the initiation and progression of atherosclerosis. Expression of cellular adhesion molecules has been reported to be inhibited by quercetin, a dietary flavonoid, but the underlying mechanisms of quercetin’s effects are still not completely understood. In this study, we found that lipopolysaccharide (LPS)-induced mRNA and protein expression of E-selectin and ICAM-1 were inhibited by quercetin in a dose-dependent manner in human aortic endothelial cells (HAEC). Levels of reactive oxygen species (ROS) in HAEC were also significantly reduced by quercetin treatment. Further study revealed that quercetin treatment time- and dose-dependently induced nuclear factor erythroid 2-related factor 2 (Nrf2) activation, increased mRNA and protein levels of heme oxygenase 1 (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutamate-cysteine ligase (GCL) catalytic (GCLC) and regulatory (GCLM) subunits. The p38 mitogen-activated protein kinase (p38) inhibitor, SB203580, significantly attenuated quercetin-induced activation of Nrf2 and expression of antioxidant enzymes. However, quercetin had no effect on Kelch-like ECH-associated protein 1 (Keap1) protein levels. In addition to increasing expression of GCL, the rate-limiting enzyme in glutathione synthesis, quercetin treatment also elevated glutathione reductase (GR) protein level and enzymatic activity and substantially altered glutathione status in HAEC. A moderate reduction followed by a complete recovery of reduced glutathione (GSH) was observed after quercetin treatment, as well as an up to 50% decline in oxidized glutathione (GSSG), resulting in an up to 70% increase in the GSH/GSSG ratio. Quercetin also induced the expression of multidrug resistance protein 1 (MRP1) and formation of quercetin-glutathione conjugates. Formation and cellular export of these quercetin-glutathione conjugates, together with induction of GCL and GR, likely account for the quercetin-induced alterations of glutathione status in HAEC. Together, my results suggest that quercetin induces activation of Nrf2 and, subsequently, induction of HO-1, NQO1, GCL, GR and MRP-1, in part, via activation of p38. Induction of antioxidant enzymes and alterations in intracellular glutathione status readily explain the antioxidant effects of quercetin against basal and LPS-induced oxidant formation in HAEC, whereas the anti-inflammatory effects of quercetin on LPS-induced adhesion molecule expression are likely due to increased expression of HO-1 and may occur through antioxidant-independent mechanisms, such as HO-1 mediated inhibition of the transcription factor activator protein-1 (AP-1).
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