Anti-atherogenic Properties of Zinc

Little is known about the requirements and function of zinc in maintaining endothelial cell integrity, especially during stressful conditions, such as the inflammatory response in cardiovascular disease. Because zinc is required for normal cellular repair processes, and because atherosclerosis is believed to begin with vessel wall injury or dysfunction, a depressed zinc status may be involved in either initiation of cell injury or inadequate vascular tissue repair. Thus, zinc requirements of the endothelium are increased during inflammatory conditions that exist in cardiovascular disease. However, protective mechanisms of zinc in maintaining normal functions of endothelial cells are still unclear and are the focus of this proposal. Because of its constant exposure to blood components, including prooxidants, inflammatory cytokines, diet-derived fats and their derivatives, the endothelium is very susceptible to oxidative stress and dysfunction. Thus, it is very likely that certain dietderived fats, especially unsaturated fats, can greatly alter the cellular lipid and oxidant/antioxidant environment and thus further compromise normal endothelial integrity during zinc deficiency. We hypothesize that zinc deficiency augments proinflammatory effects of specific fatty acids in endothelial cells that lead to increased atherogenesis. This hypothesis is strongly supported by our preliminary data. Indeed, our data suggest that zinc inhibits the pathways of signal transduction leading to an inflammatory response and to disruption of endothelial cell integrity. Furthermore, we have evidence that zinc deficiency can activate endothelial adhesion molecule expression in vivo. To test our hypothesis, we will study molecular mechanisms by which zinc deficiency promotes inflammatory responses in the endothelium. We also predict that cell enrichment with omega-6-rich unsaturated lipids will potentiate a zinc deficiency-mediated activation of endothelial cells. Finally, a ApoE knock-out mouse model, which mimics the pathology of human atherosclerosis, will be utilized to correlate the effects of dietary unsaturated fat and zinc deficiency on atherogenic markers of endothelial cell dysfunction. Results from this work will provide critical information towards the nutritive and therapeutic role of zinc in inflammatory diseases such as atherosclerosis.