Atherosclerosis, the major cause of death and disability in the United States, is a chronic disease with inflammatory components. Our overall objective is to use molecular, cellular and animal models to study how activation of NF-kappaB contributes to atherosclerosis. This nuclear transcription factor controls the expression of many genes linked to atherogenesis, including those involved with inflammation. We hypothesize that one unifying mechanisms in this complex disease is the activation of NF-kappaB. The mechanism(s) that activates NF-kappaB in atherogenesis is unknown and the effect of inhibiting NF-kappaB atherogenesis is untested in animal models. In Aim 1, we focus on shear stress and oxidized LDL-induced activation of NF-kappaB in cultured porcine endothelium and smooth muscle cells as models for determining the mechanism(s) of activation of NF-kappaB in atherogenesis. The role of phosphorylation and degradation of IkapaB and the operative kinases and signal transduction pathways will be identified. In Aim 2, we will develop and test a series of reagents that inhibit NF-kappaB activation in response to shear stress and oxidized LDL. The most promising inhibitors will be tested in Aim 3 where we will use our pigs with shear and diet-induced atherosclerosis to determine the effect of inhibiting activation of NF-kappaB. Periodontal disease has now been established as a risk factor for atherosclerosis and its thrombotic complications. It is unknown if periodontal disease contributes to the initiation or progression of atherosclerosis. NF-kappaB likely plays an essential role in bone loss due to periodontitis since IL-1beta and TNFalpha are key mediators in humans and animal models of the disease and strong activators of NF-kappaB. We hypothesize that the chronic and intense inflammatory response accompanying periodontal disease produces an excess burden of circulating mediators of inflammation that initiate or exacerbate the inflammatory components of atherosclerosis. To test this hypothesis, we will adapt a model of ligature-induced periodontitis to our pig models of atherogenesis. Our goal in Aim 4 will be to determine if the presence of periodontal inflammation contributes to the initiation and/or progression of atherosclerosis. If so, then we will determine whether or not activated NF-kappaB is present in cells in the atherosclerotic lesion that is modulated by oral inflammation. Our data on the mechanisms involved in the critical role of NF-kappaB in atherosclerosis could lead to important therapeutic applications especially as it relates to the impact of periodontitis.