THE ROLE OF ACE IN INFLAMMATION AND HYPERTENSION

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PROJECT SUMMARY A tremendous amount of published data indicates that cellular inflammation plays a critical role in the development of hypertension. In a sense, any immune challenge initiates a series of responses that are similar regardless of the initiating agent. In other words, whether challenged by the development hypertension or by infection, the initial reaction of the immune system is innate immunity. Here, monocytes, macrophages and other cells detect an initial insult and react by elaborating pro-inflammatory cytokines (TNFα, IL-12 etc) that amplify the initial response. Specific Aim 1 examines the role of angiotensin converting enzyme (ACE) in macrophage expression of cytokines during the initial (innate) immune response to hypertension. Here the focus is how the N-domain of ACE affects macrophage differentiation and the expression of pro- and anti- inflammatory cytokines. The innate response is followed by the adaptive phase of the immune response centered on the interaction of T cells with dendritic cells and other antigen presenting cells (APCs). APCs present antigenic peptides in the context of MHC molecules and evoke a variety of T cell responses. ACE is a peptidase and Specific Aim 2 is to study the role of ACE in APC activation and peptide presentation during hypertension. Ultimately, the T cells that induce pathology in hypertension are activated by specific peptide ligands that engage the T cell receptor. This is well known, but it has critical relevance to hypertension. While studies have suggested that a class of T cells called CD8+ T cells is critical to the development of hypertension, we know essentially nothing about the epitopes that become immunogenic in hypertension or about the precise CD8+ T cells that respond to these epitopes. Specific Aim 3 will address this by using the technique of T cell hybridomas to clone and study the precise T cell receptors that interact with hypertensive epitopes. This will provide a powerful new tool to study where and when immune epitopes are made during the development of hypertension. This tool will also be used to clone (and thus identify) the precise proteins that are the source of the hypertensive epitopes. These aims will greatly enhance our understanding of how the inflammatory response contributes to hypertension, and they will also provide new targets for intervention.