Role of T Cell and Vascular NADPH Oxidases in Angiotensin II Induced Hypertension

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DESCRIPTION (provided by applicant): Hypertension (HTN) is the number one attributable risk factor for death worldwide leading to increased morbidity and mortality from ischemic heart disease, heart failure, stroke, and chronic kidney disease. Reactive oxygen species (ROS) produced by the NADPH family of oxidases contributes to the pathophysiology of HTN. However, a key unresolved issue is which cell type is critical in the regulation of blood pressure (BP) and what is the relevant enzymatic/signaling pathways involved. Preliminary data from our lab suggests that T cells via a T cell NADPH oxidase are essential for HTN induced by angiotensin II (Ang II). We propose a model in which Ang II acts directly on T cells and has central effects which lead to T cell activation and that activated T cells then act on vessel walls and the kidney via infiltration and cytokine release to stimulate local NADPH oxidases which in turn promote HTN. In this proposal, we will investigate the role of the T cell NADPH oxidase vs vascular NADPH oxidases in Ang II induced HTN by addressing the following specific aims. Specific Aim 1. Define the role of the T cell NADPH oxidase in Ang II induced HTN by targeted knockout of the T cell p22phox. Using transgenic mouse models, we will create mice in which p22phox, a critical component of most types of NADPH oxidase, is deleted in T cells only. We will then determine the effect of Ang II on BP response, aortic superoxide production, and vascular reactivity. Specific Aim 2. Further elucidate the mechanism of T cell mediated HTN by determining the effect of the T cell NADPH oxidase on T cell infiltration into the vessel wall. Preliminary data from our lab showed that Ang II markedly increased the number of T cells in the adventitia and periadventitial fat and that this increase was diminished in mice with defective NADPH oxidase in all cells. In this aim, we will use mice with targeted deletion of p22phox in T cells only to determine the effect on T cell infiltration. Specific Aim 3. Define the role of the vascular smooth muscle cell (VSMC) NADPH oxidase vs the endothelial cell (EC) NADPH oxidase in Ang II induced HTN and T cell infiltration by conditional, targeted knockout of p22phox in VSMCs or ECs. The experiments described in this research proposal will further our understanding of the mechanisms by which ROS contribute to hypertension. High blood pressure is a common condition and major risk factor for heart disease, stroke, and kidney disease. The studies described in this proposal will further our understanding of the cell types and pathways involved in the development of high blood pressure and hopefully lead to better treatments for this condition.