DC isoketal-modified proteins activate T cells and promote hypertension
Annet Kirabo, … , Jackson Roberts II, David G. Harrison
Annet Kirabo, … , Jackson Roberts II, David G. Harrison
Published September 17, 2014
Citation Information: J Clin Invest. 2014;124(10):4642-4656. https://doi.org/10.1172/JCI74084.
View: Text | PDF
Research Article

DC isoketal-modified proteins activate T cells and promote hypertension

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.

Authors

Annet Kirabo, Vanessa Fontana, Ana P.C. de Faria, Roxana Loperena, Cristi L. Galindo, Jing Wu, Alfiya T. Bikineyeva, Sergey Dikalov, Liang Xiao, Wei Chen, Mohamed A. Saleh, Daniel W. Trott, Hana A. Itani, Antony Vinh, Venkataraman Amarnath, Kalyani Amarnath, Tomasz J. Guzik, Kenneth E. Bernstein, Xiao Z. Shen, Yu Shyr, Sheau-chiann Chen, Raymond L. Mernaugh, Cheryl L. Laffer, Fernando Elijovich, Sean S. Davies, Heitor Moreno, Meena S. Madhur, Jackson Roberts II, David G. Harrison

×

Figure 7

Oxidant stress and isoketals alter DC gene expression in hypertension.

Options: View larger image (or click on image) Download as PowerPoint
Oxidant stress and isoketals alter DC gene expression in hypertension. (...
(A) Microarray analysis of CD11c+ cells from spleens of WT mice infused with either sham or angiotensin II with or without 2-HOBA treatment or cotreatment with a combination of hydralazine and hydrochlorothiazide as well as cells from spleens of Nox2–/– mice. The gene expression profiles for the various treatment groups. (B) Genes altered by angiotensin II (blue), genes reversed by Nox2–/– (pink), genes reversed by 2-HOBA treatment (green), and a Venn diagram summarizing altered genes, including those normalized in both Nox2–/– and 2-HOBA–treated groups. (C) Normalization of angiotensin II–induced hypertension by cotreatment with a combination of hydralazine and hydrochlorothiazide. (D) Volcano plot showing the 505 genes altered by angiotensin II compared with sham and colored by P value. Red represents high and blue represents low P values in WT angiotensin II vs. WT sham. Color codes for each gene in D were used in E–G. The genes altered by angiotensin II in C but plotted based on how these genes behaved (E) after 2-HOBA treatment, (F) in Nox2–/– mice, and (G) after treatment with a combination of hydralazine and hydrochlorothiazide, when compared with WT sham (n = 6, **P < 0.01)