Abstract 57: Natural Killer Cells Drive Angiotensin II-Induced Vascular Dysfunction Dependent on the T-bet/IFN-gamma Axis

Rationale Immune cells contribute to angiotensin II (ATII) induced vascular dysfunction and inflammation. However, the mechanisms of recruitment and immune effector pathways remain incompletely understood. Objective We tested the hypothesis that interferon-gamma (IFN-γ) and natural killer (NK) cells play a pivotal role in ATII-driven vascular inflammation. Methods and results IFN-γ -/- and Tbx21 -/- mice were partially protected from ATII-induced vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-bet, the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of NADPH oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1 and interleukin 12 in aortas of ATII-infused mice. Compared to controls, IFN-γ -/- and Tbx21 -/- mice were characterized by reduced ATII-mediated vascular recruitment of both NK1.1 + NK-cells as the major producers of IFN-γ and CD11b + Gr-1 low IL-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet + LysM + myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production. Conclusion We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte-NK-cell activation as potential therapeutic targets in cardiovascular disease.