title: Angiotensin II-induced vascular dysfunction depends on interferon-γ-driven immune cell recruitment and mutual activation of monocytes and NK-cells.
abstract: OBJECTIVE
  Immune cells contribute to angiotensin II (ATII)-induced vascular dysfunction and inflammation. Interferon-γ (IFN-γ), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-γ remain incompletely understood.
  
  
  RESULTS
  IFN-γ(-/-) and Tbx21(-/-) mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of nicotinamide adenosine dinucleotide phosphate oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1, and interleukin-12 in aortas of ATII-infused mice. Compared with controls, IFN-γ(-/-) and Tbx21(-/-) mice were characterized by reduced ATII-mediated vascular recruitment of both natural killer (NK)1.1(+) NK-cells as the major producers of IFN-γ and CD11b(+)Gr-1(low) interleukin-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet(+)lysozyme M(+) myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 2nd Medical Clinic, Center for Thrombosis and Hemostasis, University Medical Center of Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kossmann
authors.forename: Melanie
authors.initials: M
authors.lastname: Schwenk
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Susanne H
authors.initials: SH
authors.lastname: Karbach
authors.forename: Maria I
authors.initials: MI
authors.lastname: Schmidgen
authors.forename: Moritz
authors.initials: M
authors.lastname: Brandt
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.forename: Hanhan
authors.initials: H
authors.lastname: Hu
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönfelder
authors.forename: Stephan
authors.initials: S
authors.lastname: Grabbe
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D018384:Oxidative Stress / Q000276:immunology / Q000502:physiology; D011897:Random Allocation; D012016:Reference Values; D014652:Vascular Diseases / Q000276:immunology / Q000378:metabolism*
chemical_list: D000804:Angiotensin II; D007371:Interferon-gamma
keywords: angiotensin II; inflammation; interferon-γ; natural killer cells; oxidative stress; vascular function