The long term goal of our research is to understand the how vascular cells produce reactive oxygen species (ROS), and what the consequences of vascular ROS production are in vivo. We have previously demonstrated that ROS, and specifically those produced by NADPH oxidases are important in the pathogenesis of hypertension. Recently, in an attempt to understand what cell types mediate this effect, we have shown that angiotensin ll-induced hypertension is markedly blunted in Rag-1""""""""/~ mice. These mice lack both T and B cells. When we reconstitute these mice with T cells, this completely normalizes the hypertensive effect of angiotensin II, while adoptive transfer of B cells has no effect. Moreover, if we perform adoptive transfer of T cells that lack the NADPH oxidase subunit p47prtox, this only partly restores the hypertensive response. These data indicate that the T cell, and in particular the T cell NADPH oxidase plays a critical role in the development of hypertension. In our planned studies, we will attempt to gain insight into how T cells cause hypertension.
In aim 1, we will determine how angiotensin II stimulates T cell activation and if ROS produced by the NADPH oxidase mediates this effect by studying T cells in culture.
In aim 2, we will determine if central actions of angiotensin II are important for T cell activation in vivo. In this aim, we will perform ablation of the AV3V region and also specifically delete the NADPH oxidase subunit p22phox in the circumventricular organs.
In aim 3, we will examine what characteristics of T cells in vivo are important in mediating hypertension by performing adoptive transfer of T cells from mice lacking either the AT1 receptor, the beta2 adrenergic receptor or CCR5 or by targeting deletion of the T cell NADPH oxidase.
In aim 4, we will determine the role of the endothelial vs. vascular smooth muscle NADPH oxidases in the response to T cell activation and angiotensin II. These studies will be greatly aided by unique animal models, including a mouse we have recently created that will allow targeted deletion of the NADPH oxidase subunit p22p/10J (in specific tissues and cells. Hypertension remains a major source of morbidity and mortality in Western societies and the mechanisms underlying this disease are not completely understood. Our planned studies promise to provide new understanding of the mechanisms underlying this disease, and may provide new treatment targets for high blood pressure.
| Loperena, Roxana; Van Beusecum, Justin P; Itani, Hana A et al. (2018) Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide. Cardiovasc Res 114:1547-1563 |
| Norlander, Allison E; Madhur, Meena S; Harrison, David G (2018) The immunology of hypertension. J Exp Med 215:21-33 |
| Tran, Anh Nhat; Walker, Kiera; Harrison, David G et al. (2018) Reactive species balance via GTP cyclohydrolase I regulates glioblastoma growth and tumor initiating cell maintenance. Neuro Oncol 20:1055-1067 |
| Pandey, Arvind K; Singhi, Eric K; Arroyo, Juan Pablo et al. (2018) Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease. Hypertension 71:e1-e8 |
| Dikalova, Anna E; Itani, Hana A; Nazarewicz, Rafal R et al. (2017) Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension. Circ Res 121:564-574 |
| Foss, Jason D; Kirabo, Annet; Harrison, David G (2017) Do high-salt microenvironments drive hypertensive inflammation? Am J Physiol Regul Integr Comp Physiol 312:R1-R4 |
| Guzik, Tomasz J; Skiba, Dominik S; Touyz, Rhian M et al. (2017) The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res 113:1009-1023 |
| Grome, Heather N; Barnett, Louise; Hagar, Cindy C et al. (2017) Association of T Cell and Macrophage Activation with Arterial Vascular Health in HIV. AIDS Res Hum Retroviruses 33:181-186 |
| Loperena, Roxana; Harrison, David G (2017) Oxidative Stress and Hypertensive Diseases. Med Clin North Am 101:169-193 |
| Oh, Young S; Berkowitz, Dan E; Cohen, Richard A et al. (2017) A Special Report on the NHLBI Initiative to Study Cellular and Molecular Mechanisms of Arterial Stiffness and Its Association With Hypertension. Circ Res 121:1216-1218 |
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