DC isoketal-modified proteins activate T cells and promote hypertension

Kirabo, A. et al. (2014) DC isoketal-modified proteins activate T cells and promote hypertension. Journal of Clinical Investigation, 124(10), pp. 4642-4656. (doi: 10.1172/JCI74084) (PMID:25244096) (PMCID:PMC4220659)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Guzik, Professor Tomasz
Authors: Kirabo, A., Fontana, V., de Faria, A. P.C., Loperena, R., Galindo, C. L., Wu, J., Bikineyeva, A. T., Dikalov, S., Xiao, L., Chen, W., Saleh, M. A., Trott, D. W., Itani, H. A., Vinh, A., Amarnath, V., Amarnath, K., Guzik, T. J., Bernstein, K. E., Shen, X. Z., Shyr, Y., Chen, S.-c., Mernaugh, R. L., Laffer, C. L., Elijovich, F., Davies, S. S., Moreno, H., Madhur, M. S., Roberts, J., and Harrison, D. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238
Published Online:17 September 2014

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