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Superoxide and Isoketal formation in Dendritic Cells from Hypertensive mice activate T cells and promote Hypertension
Author(s) -
Kirabo Annet,
Galindo Cristi,
Wu Jing,
Thabet Salim,
Bikineyeva Alfiya,
Dikalov Sergey,
Amarnath Venkataraman,
Davies Sean,
Roberts Jackson L,
Harrison David Glenn
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.708.7
Subject(s) - angiotensin ii , dendritic cell , nadph oxidase , superoxide , chemistry , antigen presenting cell , t cell , inflammation , oxidative stress , cd8 , immunology , antigen , immune system , endocrinology , medicine , receptor , biochemistry , enzyme
Oxidative injury and inflammation have been implicated in the genesis of hypertension but the mechanisms involved are not fully understood. We examined the hypothesis that oxidative stress in dendritic cells alters endogenous proteins via Isoketal‐modification leading to formation of neo‐antigens, T cell activation and a predisposition to blood pressure elevation. Dendritic cells isolated from mice with angiotensin II‐induced hypertension had a 5‐fold increase in NADPH oxidase‐dependent superoxide production when compared to sham‐treated mice (334.0±49.7 versus 65.8±4.5 pmol/mg protein). This was associated with an accumulation of Isoketals and activation of IL‐1b and IL‐6 production in these cells. Microarray analysis revealed a predominant alteration in expression of genes involved in cell‐mediated immunity and antigen processing in dendritic cells from hypertensive mice. Treatment with a potent Isoketal scavenger, 2‐hydroxybenzylamine, markedly attenuated angiotensin II‐induced hypertension (142.59 ± 8.98 mmHg versus 175.53 ± 5.19 mmHg in controls). Adoptive transfer of dendritic cells from hypertensive mice polarized T cells from naïve recipients to IL‐17 and IFN‐γ producing CD8 + cells and also primed development of hypertension in mice given a sub‐pressor dose of angiotensin II (157.45 ± 33.86 mmHg versus 119.90 ± 17.33 mmHg in controls). These studies show that angiotensin II‐induced hypertension activates dendritic cells, in large part by causing superoxide production and formation of Isoketals. We propose that Isoketal‐modified proteins can be presented as neoantigens by dendritic cells, which in turn trigger T cell activation leading to hypertension.