Abstract 18207: Angiotensin II-induced Vascular Dysfunction is Promoted by Innate Immune Cells via Vascular IFN-γ-Production
Background: Innate and adaptive immune cells contribute to vascular inflammation in angiotensin II (ATII) induced arterial hypertension. However, the mechanisms of recruitment and cooperation of immune effector pathways contributing to ATII-induced vascular inflammation are unknown.
Methods and results: Interferon gamma (IFN-γ) and the Th1 transcription factor T-bet are induced by ATII in mouse aorta. IFN-γ-/- and T-bet-/- mice are partially protected from ATII induced vascular injury (1mg/kg/d for 7d), whereas mice constitutively overexpressing IFN-γ have a phenotype of vascular dysfunction. ATII induces a systemic Th1 like polarization pattern in CD4+ cells, which is shut off in T-bet-/- mice marked by a loss of IFN-γ formation. Flow cytometry analysis revealed, that ATII increases the amount of IFN-γ producing lymphoid and myelomonocytic cells in aortic tissue lysates, and T-bet deficiency was associated with reduced numbers of Cd11b+Gr-1high neutrophils, Cd11b+Gr-1low monocytes, NK1.1+ natural killer cells and T-cell receptor β (TCRβ)+ cells recruited form the circulation. NK1.1+ cells as the most T-bet positive immune cell in the vasculature do not directly respond to ATII to release IFN-γ, but rather to IL12 and IL18. By selective depletion and adoptive transfer experiments we demonstrate, that T-bet+LysM+ myelomonocytic cells are essential to facilitate IFN-γ formation of NK-cells and T-cells and that NK1.1+ cells are important contributors of ATII-induced vascular inflammation.
Conclusion: IFN-γ exerts a previously unrecognized level of control over immune cell entry and effector competence in ATII-induced vascular inflammation and suggest molecules regulating IFN-γ expression as novel targets in the treatment of cardiovascular disease.
- © 2012 by American Heart Association, Inc.