Dendritic cell superoxide and isoketals activate T cells and promote angiotensin II hypertension (1153.2)

Oxidative injury and inflammation contribute to the genesis of hypertension but the mechanisms involved are not fully understood. We describe a new pathway where angiotensin II promotes dendritic cell (DC) activation of T cells and ultimately hypertension. NADPH oxidase‐dependent superoxide production is increased 5‐fold in DCs from hypertensive mice. This is associated with DC accumulation of protein‐isoketal adducts (isoketals are highly reactive γ‐ketoaldehydes produced via the isoprostane pathway of free radical mediated lipid peroxidation) and production of IL‐6, IL‐1β and IL‐23. DCs from hypertensive but not sham mice promote survival and proliferation of CD8+ T cells. Chemically diverse isoketal scavengers not only prevent activation and immunogenicity of DCs, but also attenuate angiotensin II hypertension (142.59 ± 8.98 mmHg vs. 175.53 ± 5.19 mmHg in controls). Moreover, adaptive transfer of DCs from hypertensive mice prime development of hypertension in response to a subpressor dose of angiotensin II (157.45 ± 33.86 mmHg vs. 119.90 ± 17.33 mmHg in controls). 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 when compared to well‐controlled and normotensive subjects (23.2±11.5 vs. 18.3±10.3 vs. 11.6±7.0 pg/mL, p<0.05). We conclude that angiotensin II‐induced hypertension activates DCs, in large part by causing superoxide production and formation of isoketals. These studies define a new mechanism of hypertension and identify a potential new therapeutic approach for this disease. Grant Funding Source : AHA Post‐Doctoral Fellowship (13POST14440041), R01HL039006, R01HL105294, P01HL095070, P01GM015431