DC isoketal-modified proteins activate T cells and promote hypertension.

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, Harrison DG
J Clin Invest. 2014 124 (10): 4642-56

PMID: 25244096 · PMCID: PMC4220659 · DOI:10.1172/JCI74084

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.

MeSH Terms (29)

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-1beta Interleukin-6 Interleukin-17 Interleukin-23 Kidney Lymphocyte Activation Male Mice Mice, Transgenic Middle Aged Oxidative Stress Oxygen Superoxides T-Lymphocytes

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