Vascular endothelium forms a dynamic interface between blood elements and peripheral tissues. Endothelial cells can undergo changes in function that are critical to normal physiological processes, and nonadaptive alterations that are important in atherogenesis. Multiple genes relevant to the initiation of the atherosclerotic lesion have functional nuclear factor-kappaB) elements. Activation of this transcription factor may coordinate the expression of numerous endothelia products which are important in the initiation and progression of atherosclerotic lesions. Increased expression of the NF-kappaB inhibitors decreases NF-kappaB activation and diminishes expression of kappaB-dependent genes. This regulatory mechanism insures that induction of kappaB is transient and that the activated endothelial cell returns to a quiescent state. This dynamic balance may be offset by the agents associated with the onset of atherogenesis. A series of interrelated studies are proposed under three Specific Aims to test the hypothesis that the NF-kappaB/IkappaB autoregulatory system plays an important role in the formation of atherosclerotic lesions. Multiple proatherogenic agents that can activate NF-kappaB use different signal transduction pathways that all converge on one common target, IkappaB-alpha. Inducible phosphorylation of this constitutively phosphorylated inhibitor leads to degradation of the inhibitor and subsequent translocation of the transcriptional activator into the nucleus. In the First Specific Aim, both the constitutive and the inducible kinases controlling activation of the transcription factor system will be identified and putatively novel kinases molecularly cloned. In the Second Specific Aim, the activation state of the transcription factor system will be correlated with initiation and progression of atherosclerotic lesions in both an animal model and human specimens. In the Third Specific Aim, the relevance of this regulatory system to atherosclerotic lesion formation in vivo will be tested in atherosclerosis-susceptible murine models. Atherosclerosis will be examined in animals with targeted mutations in the p50 component of NF-kappaB, and in transgenic animals in which IkappaB-alpha expression is specifically dysregulated in endothelial cells. The results of these studies should determine the role of the NF-kappaB/IkappaB autoregulatory system in the initiation and progression of atherogenesis.
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