The overall goal of our research program is to understand factors that modulate vascular function in the setting of diseases such as hypertension. Recently, we made an observation linking oxidant stress with inflammation, vascular dysfunction and hypertension. We have found that RAG-1""""""""'"""""""" mice, which lack both T and B lymphocytes, develop a very blunted hypertensive response to either chronic low-dose angiotensin II infusion or DOCA-salt challenge. Moreover, adoptive transfer of T, but not B cells completely restores the hypertensive caused by these challenges. Thus, the T lymphocyte is essential for the development of hypertension. Our preliminary data also show that angiotensin II stimulates an increase in T cell levels of the chemokine receptor CCR5 and vascular levels of its ligand RANTES and that this is associated with a marked infiltration of CCR5+ T cells into the vessel, and in particular the periadventitial fat and the adventitia. In our project, we will pursue 3 aims.
In aim 1, we will determine the importance of the CCR5/RANTES interaction in development of hypertension and vascular dysfunction by inducing hypertension in mice lacking either RANTES or CCR5. These studies will allow us to understand if CCR1 might also play a role in hypertension and to determine if a modified RANTES (Met-RANTES) can be used to prevent T cell infiltration into vessels and to reduce blood pressure. We find that the NADPH oxidase is important for T cell infiltration into the vessel, but it is unclear if this is mediated by ROS produced in the endothelium, the vascular smooth muscle or the adipose cells. To address this, we will create mice selectively lacking the NADPH oxidase subunit p22pft?* in these cells using Cre lox technology and mice with floxed p22p/JOX that we have already created.
In aim 3, we will attempt to determine if human T cells home to either human fat or vessels by implanting human tissue in SCID mice and performing adoptive transfer of autologous T cells one week later. We will also determine if angiotensin II stimulates human T cell homing in human vessels or perivascular fat and if this is dependent on reactive oxygen species or RANTES. Overall, these studies promise to provide new information about the inflammatory response that occurs in the setting of hypertension and about the pathophysiology of this common disease. This project will interact with our other PPG projects very closely. We are making mice lacking P22P/10X in specific cells that will be used by Drs. Dudley. Dr. Dudley's project will utilize methods that are commonly employed in our laboratory and we will assist with these. Our new research direction has been enormously aided by collaborations with Dr. Weyand, the project director of project 2 and her co-investigator Dr. Goronzy. Dr. Weyand will assist with our studies of human tissue implants in SCID mice and we will provide assistance with angiotensin II infusion models in her experiments. Our project will also greatly depend on the services provided by Cores A and B as we will rely heavily on measurements of O2~ and other ROS and also immunostaining of vessels and tissue implants. Dr. Lin and his team are an excellent source of human tissue which we can use in aim 3. Finally, Dr. Tomasz J. Guzik, who has been a visiting professor at Emory, will continue to serve as a consultant and serve on our external advisory board. Dr. Guzik has proven to be an excellent collaborator.
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|Loperena, Roxana; Harrison, David G (2017) Oxidative Stress and Hypertensive Diseases. Med Clin North Am 101:169-193|
|Yanes, Rolando E; Gustafson, Claire E; Weyand, Cornelia M et al. (2017) Lymphocyte generation and population homeostasis throughout life. Semin Hematol 54:33-38|
|Weyand, Cornelia M; Zeisbrich, Markus; Goronzy, Jörg J (2017) Metabolic signatures of T-cells and macrophages in rheumatoid arthritis. Curr Opin Immunol 46:112-120|
|Wu, Jing; Saleh, Mohamed A; Kirabo, Annet et al. (2016) Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest 126:50-67|
|Fang, Fengqin; Yu, Mingcan; Cavanagh, Mary M et al. (2016) Expression of CD39 on Activated T Cells Impairs their Survival in Older Individuals. Cell Rep 14:1218-1231|
|Li, Yinyin; Shen, Yi; Hohensinner, Philipp et al. (2016) Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis. Immunity 45:903-916|
|Wen, Zhenke; Shimojima, Yasuhiro; Shirai, Tsuyoshi et al. (2016) NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs. J Clin Invest 126:1953-67|
|Itani, Hana A; McMaster Jr, William G; Saleh, Mohamed A et al. (2016) Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans. Hypertension 68:123-32|
|Shirai, Tsuyoshi; Nazarewicz, Rafal R; Wallis, Barbara B et al. (2016) The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med 213:337-54|
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