Although studies in animal models of hypertension have demonstrated a key role for T cells, it has been unclear how T cells are activated under hypertensive conditions. A new study identifies protein oxidation by isoketals, which are derived from free radical–mediated lipid peroxidation of arachidonic acid, as contributing to T cell activation and hypertension (J. Clin. Invest. 124, 4642–4656, 2014).
David Harrison and his colleagues found in two mouse models of hypertension—treatment with either angiotensin II or deoxycorticosterone plus NaCl—that isoketal-modified proteins accumulated within splenic dendritic cells. For either model, treatment with an isoketal scavenger blunted the hypertensive response. Moreover, adoptive transfer of isoketal-laden dendritic cells sensitized the recipient mice to a low, subpressor dose of angiotensin II—an effect that required the presence of T cells in the recipient mice—indicating the pathological role of this oxidized lipid in dendritic cells. Mechanistic studies showed that accumulation of isoketal-modified proteins in dendritic cells as a consequence of either oxidative stress within the cells or uptake of modified proteins led to increased cytokine production and T cell activation in coculture studies. The authors also showed that hypertensive patients have increased levels of plasma F2-isoprostanes, which are generated in the same pathway as isoketals, and of isoketal adducts in circulating mononuclear cells.
These findings link oxidative stress to the formation of neoepitopes that promote an autoimmune-like response, leading to hypertension.
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Basson, M. T cell activation in hypertension. Nat Med 20, 1241 (2014). https://doi.org/10.1038/nm.3752