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      Elevated Eosinophils as a Feature of Inflammation Associated With Hypertension in Virally Suppressed People Living With HIV

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          Abstract

          Background

          People living with HIV ( PLWH) are at increased risk of cardiovascular disease, including hypertension, which persists despite effective plasma viral suppression on antiretroviral therapy. HIV infection is characterized by long‐term alterations in immune function, but the contribution of immune factors to hypertension in PLWH is not fully understood. Prior studies have found that both innate and adaptive immune cell activation contributes to hypertension.

          Methods and Results

          We hypothesized that chronic inflammation may contribute to hypertension in PLWH. To test this hypothesis, we enrolled a cohort of 70 PLWH (44% hypertensive) on a long‐term single antiretroviral therapy regimen for broad phenotyping of inflammation biomarkers. We found that hypertensive PLWH had higher levels of inflammatory cytokines, including tumor necrosis factor‐α receptor 1, interleukin‐6, interleukin‐17, interleukin‐5, intercellular adhesion molecule 1 and macrophage inflammatory protein‐1α. After adjustment for age, sex, and fat mass index, the circulating eosinophils remained significantly associated with hypertension. On the basis of these results, we assessed the relationship of eosinophils and hypertension in 2 cohorts of 50 and 81 039 similar HIV‐negative people; although eosinophil count was associated with prevalent hypertension, this relationship was abrogated by body mass index.

          Conclusions

          These findings may represent a unique linkage between immune status and cardiovascular physiological characteristics in HIV infection, which should be evaluated further.

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          Most cited references42

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          Inflammation, immunity, and hypertensive end-organ damage.

          For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
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            Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction.

            We have shown previously that T cells are required for the full development of angiotensin II-induced hypertension. However, the specific subsets of T cells that are important in this process are unknown. T helper 17 cells represent a novel subset that produces the proinflammatory cytokine interleukin 17 (IL-17). We found that angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media. To determine the effect of IL-17 on blood pressure and vascular function, we studied IL-17(-/-) mice. The initial hypertensive response to angiotensin II infusion was similar in IL-17(-/-) and C57BL/6J mice. However, hypertension was not sustained in IL-17(-/-) mice, reaching levels 30-mm Hg lower than in wild-type mice by 4 weeks of angiotensin II infusion. Vessels from IL-17(-/-) mice displayed preserved vascular function, decreased superoxide production, and reduced T-cell infiltration in response to angiotensin II. Gene array analysis of cultured human aortic smooth muscle cells revealed that IL-17, in conjunction with tumor necrosis factor-alpha, modulated expression of >30 genes, including a number of inflammatory cytokines/chemokines. Examination of IL-17 in diabetic humans showed that serum levels of this cytokine were significantly increased in those with hypertension compared with normotensive subjects. We conclude that IL-17 is critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction and might be a therapeutic target for this widespread disease.
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              Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension.

              Elevated levels of pro-inflammatory cytokine interleukin-17A (IL-17) are associated with hypertensive autoimmune diseases; however, the connection between IL-17 and hypertension is unknown. We hypothesized that IL-17 increases blood pressure by decreasing endothelial nitric oxide production. Acute treatment of endothelial cells with IL-17 caused a significant increase in phosphorylation of the inhibitory endothelial nitric oxide (NO) synthase residue threonine 495 (eNOS Thr495). Of the kinases known to phosphorylate eNOS Thr495, only inhibition of Rho-kinase prevented the IL-17-induced increase. IL-17 caused a threefold increase in the Rho-kinase activator RhoA, and this was prevented by an IL-17 neutralizing antibody. In isolated mouse aortas, IL-17 significantly increased eNOS Thr495 phosphorylation, induced RhoA expression, and decreased NO-dependent relaxation responses, all of which were prevented by either an IL-17 neutralizing antibody or inhibition of Rho-kinase. In mice, IL-17 treatment for 1 week significantly increased systolic blood pressure and this was associated with decreased aortic NO-dependent relaxation responses, increased eNOS Thr495 phosphorylation, and increased RhoA expression. Inhibition of Rho-kinase prevented the hypertension caused by IL-17. These data demonstrate that IL-17 activates RhoA/Rho-kinase leading to endothelial dysfunction and hypertension. Inhibitors of IL-17 or Rho-kinase may prove useful as anti-hypertensive drugs in IL-17-associated autoimmune diseases.
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                Author and article information

                Contributors
                annet.kirabo@vanderbilt.edu
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                17 February 2020
                18 February 2020
                : 9
                : 4 ( doiID: 10.1002/jah3.v9.4 )
                : e011450
                Affiliations
                [ 1 ] School of Medicine and Health Sciences Mulungushi University Livingstone Zambia
                [ 2 ] Department of Biomedical Sciences School of Health Sciences University of Zambia Lusaka Zambia
                [ 3 ] Vanderbilt Institute for Global Health Vanderbilt University Medical Center Nashville TN
                [ 4 ] Division of Clinical Pharmacology Vanderbilt University Medical Center Nashville TN
                [ 5 ] Department of Epidemiology and Biostatistics School of Public Health University of Zambia Lusaka Zambia
                [ 6 ] Department of Medical Education Development University of Zambia Lusaka Zambia
                [ 7 ] Department of Health Policy and Management School of Public Health University of Zambia Lusaka Zambia
                [ 8 ] Department of Biostatistics Vanderbilt University Medical Center Nashville TN
                [ 9 ] Division of Infectious Diseases Vanderbilt University Medical Center Nashville TN
                [ 10 ] Department of Molecular Physiology and Biophysics Vanderbilt University Nashville TN
                Author notes
                [*] [* ] Correspondence to: Annet Kirabo, DVM, MSc, PhD, Vanderbilt University, Room 536, Robinson Research Bldg, Nashville, TN 37232‐6602. E‐mail: annet.kirabo@ 123456vanderbilt.edu
                Article
                JAH34782
                10.1161/JAHA.118.011450
                7070208
                32064996
                024eadd9-3d1c-4618-82f1-e408933509e2
                © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 13 February 2019
                : 19 December 2019
                Page count
                Figures: 4, Tables: 2, Pages: 11, Words: 8470
                Funding
                Funded by: Fogarty International Center of the National Institutes of Health
                Award ID: D43 TW009744
                Funded by: National Institute of Allergy and Infectious Diseases , open-funder-registry 10.13039/100000060;
                Award ID: K23 AI100700
                Funded by: National Center for Advancing Translational Sciences , open-funder-registry 10.13039/100006108;
                Award ID: UL1 TR002243
                Funded by: Tennessee Center for AIDS Research
                Award ID: P30 AI110527
                Funded by: National Heart, Lung, and Blood Institute , open-funder-registry 10.13039/100000050;
                Award ID: K01HL130497
                Categories
                Original Research
                Original Research
                Hypertension
                Custom metadata
                2.0
                18 February 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.6.1 mode:remove_FC converted:04.03.2020

                Cardiovascular Medicine
                eosinophilia,hiv,hypertension,inflammation,interleukin‐5
                Cardiovascular Medicine
                eosinophilia, hiv, hypertension, inflammation, interleukin‐5

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