The association of a healthy diet and prevention of chronic inflammatory diseases has long been recognized. An important example are the soy- isoflavones, consumption of which is associated with a decrease in the incidence of atherosclerosis. Central to the beneficial effects of these compounds are their interactions with reactive oxygen (ROS) and nitrogen species (RNS) that are generated both endogenously and via environmental exposure. Little is known, however, on the biological effects of the products of these reactions. It is proposed herein that derivatives of isoflavones, obtained after reaction with inflammatory oxidants, have potent anti- atherogenic effects. Oxidative modification of low-density lipoprotein (LDL) and subsequent effects on vascular cell function are key elements of atherogenesis. Inhibition of LDL oxidation and modulation of cell signaling pathways have been proposed as key anti-atherogenic mechanisms for the isoflavones. In this proposal, these concepts are extended and the potential anti-atherogenic roles of novel derivatives of isoflavones formed at sites of inflammation (namely chlorinated and nitrated isoflavones) explored. This is important since isoflavones in their native form are poor inhibitors of LDL oxidation in vitro, yet their consumption is associated with a decrease in lipid peroxidation. Furthermore, the effects of isoflavones on key inflammatory signaling pathways involved in atherogenesis are poorly defined and in some instances pro-inflammatory effects demonstrated. Specifically, native isoflavones have been shown to stimulate monocyte-endothelial cell interactions, an early event in lesion formation. Based on the concepts discussed above and preliminary data presented herein, the investigators hypothesize that the anti-atherogenic effects of soy-isoflavones are mediated by products derived from their reactions with ROS and RNS. This hypothesis will be pursued by testing the specific aims to determine the effect of native and modified isoflavones on: (1) LDL oxidation, (2) oxLDL and ROS/RNS-induced cell death in vascular endothelial cells, and (3) oxLDL-dependent monocyte firm adhesion to endothelial cells. These studies will yield novel insights into the interplay between isoflavones and ROS/RNS that impact on both direct anti-oxidant properties, and more subtle effects on inflammatory cell signaling pathways. Also, it is anticipated that mechanistic insights gained will provide information on possible herapeutic development of isoflavones and other polyphenols.
| Chacko, Balu K; Chandler, Robert T; Mundhekar, Ameya et al. (2005) Revealing anti-inflammatory mechanisms of soy isoflavones by flow: modulation of leukocyte-endothelial cell interactions. Am J Physiol Heart Circ Physiol 289:H908-15 |
| Boersma, Brenda J; D'Alessandro, Tracy; Benton, Matthew R et al. (2003) Neutrophil myeloperoxidase chlorinates and nitrates soy isoflavones and enhances their antioxidant properties. Free Radic Biol Med 35:1417-30 |
| Fenster, Catherine P; Weinsier, Roland L; Darley-Usmar, Victor M et al. (2002) Obesity, aerobic exercise, and vascular disease: the role of oxidant stress. Obes Res 10:964-8 |
