CELLULAR VITAMIN E STATUS AND INTEGRIN FUNCTION

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This proposal is based upon the hypothesis that leukocyte and platelet vitamin E content is an important determinant of vascular inflammation through its action on beta 2 and beta 3 integrin function. This hypothesis is important because experimental, clinical and pathologic studies have established a role for inflammation in vascular disease such as atherosclerosis and the response to arterial injury. Inflammatory cell-cell and cell-matrix interactions are orchestrated by cell adhesion molecules and considerable experimental effort has demonstrated that the balance between vascular cell antioxidant status and oxidative stress is involved in the regulation of vascular cell adhesion molecules. However, the effect of antioxidant status on leukocyte and platelet integrin counter-receptors for these vascular cell adhesion molecules has been largely overlooked. Preliminary data from our laboratories indicates that vitamin E potently inhibits the function of beta 2 integrins in monocytes and beta 3 integrins in platelets. The goal of this proposal, therefore, is to define the role of cellular vitamin E, the principal lipid-soluble antioxidant in humans, on integrin function in leukocytes and platelets. The primary experimental models for this proposal will be cultured human monocytic cells (U937 and THP-1) and neutrophils, as well as freshly isolated human platelets. To achieve the goal of this project, we will finish characterizing inhibitor action of vitamin E on beta 2 integrin-dependent monocyte adhesion using agonists relevant to vascular disease including oxidants. The characterization will be extended to human neutrophils and platelets, two important mediators of vascular inflammation and the response to injury. Once this characterization is established, the investigators will investigate candidate mechanisms focusing primarily on intracellular calcium transients and protein kinase C phosphorylation status, two vitamin E targets identified in our preliminary data. Finally, the PIs will establish the physiologic relevance of their findings by testing the activity of vitamin E on vascular inflammation and neointimal growth using a newly developed murine model of arterial injury that we have established to be dependent on platelet deposition and beta 2 integrin function. Collectively, these studies should shed light on the control of vascular inflammation and provide the insights necessary to design important new strategies for the modulation of vascular disease, an important source of morbidity and mortality in the world today.