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 (TNF?, 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.

Public Health Relevance

Hypertension and inflammation go hand-in-hand to the extent that understanding inflammatory processes is critical to understanding and controlling many negative aspects of hypertension. ACE plays a direct role in influencing several different aspects of the immune response. Understanding the role of ACE in inflammation and hypertension will provide new opportunities for controlling hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL129941-01A1
Application #
9143873
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2021-07-31
Budget Start
2016-08-01
Budget End
2017-07-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Li, You; Shen, Xiao Z; Li, Liang et al. (2017) Brain Transforming Growth Factor-? Resists Hypertension Via Regulating Microglial Activation. Stroke 48:2557-2564
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
Khan, Zakir; Shen, Xiao Z; Bernstein, Ellen A et al. (2017) Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood 130:328-339
Kim, C; Fang, F; Weyand, C M et al. (2017) The life cycle of a T cell after vaccination - where does immune ageing strike? Clin Exp Immunol 187:71-81
Goronzy, Jörg J; Weyand, Cornelia M (2017) Successful and Maladaptive T Cell Aging. Immunity 46:364-378
Loperena, Roxana; Harrison, David G (2017) Oxidative Stress and Hypertensive Diseases. Med Clin North Am 101:169-193
Watanabe, Ryu; Hosgur, Ebru; Zhang, Hui et al. (2017) Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis. Joint Bone Spine 84:421-426
Weyand, Cornelia M; Berry, Gerald J; Goronzy, Jörg J (2017) The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease. J Leukoc Biol :
Li, Yinyin; Goronzy, Jörg J; Weyand, Cornelia M (2017) DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system. Exp Gerontol :
Zhang, Hui; Watanabe, Ryu; Berry, Gerald J et al. (2017) Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A 114:E970-E979

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