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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^sup +^ 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.
Introduction
It is well established that inflammation is involved in the genesis of hypertension (1). T cells and macrophages accumulate in the kid- neys and vasculature of animals with experimental hypertension and likely contribute to the end-organ damage that accompanies this disease (2, 3). Immunosuppression ameliorates end-organ damage resulting from hypertension, and the renin-angioten- sin system has been reported to regulate immune responses (4). Previous studies from our laboratory and others have shown that cells of the adaptive immune system are involved in the genesis of hypertension (5). Mice lacking lymphocytes (Rag1-/- mice) develop blunted hypertension and are protected from vascular dysfunc- tion and vascular oxidative stress in response to various stimuli, including angiotensin II, norepinephrine, and deoxycorticoster- one acetate plus NaCl (DOCA-salt). Adoptive transfer of T cells, but not B cells, restores hypertension in these animals. In addi- tion, mice with severe combined immunodeficiency are protected from experimental hypertension (6), as are mice lacking the T cell cytokine IL-17A (7). The triggering events that lead to T cell activa- tion in hypertension are currently not known.
Antigen-presenting dendritic cells (DCs) capture...