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DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest 2014 Oct;124(10):4642-56

Date

09/23/2014

Pubmed ID

25244096

Pubmed Central ID

PMC4220659

DOI

10.1172/JCI74084

Scopus ID

2-s2.0-84907494957   263 Citations

Abstract

Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.

Author List

Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, Bikineyeva AT, Dikalov S, Xiao L, Chen W, Saleh MA, Trott DW, Itani HA, Vinh A, Amarnath V, Amarnath K, Guzik TJ, Bernstein KE, Shen XZ, Shyr Y, Chen SC, Mernaugh RL, Laffer CL, Elijovich F, Davies SS, Moreno H, Madhur MS, Roberts J 2nd, Harrison DG



MESH terms used to index this publication - Major topics in bold

Aged
Aldehydes
Angiotensin II
Animals
Antigen-Presenting Cells
B7-1 Antigen
B7-2 Antigen
Cell Proliferation
Cohort Studies
Dendritic Cells
Female
Gene Expression Regulation
Humans
Hypertension
Inflammation
Interleukin-17
Interleukin-1beta
Interleukin-23
Interleukin-6
Kidney
Lymphocyte Activation
Male
Mice
Mice, Transgenic
Middle Aged
Oxidative Stress
Oxygen
Superoxides
T-Lymphocytes