The T Helper 1 Transcription Factor T Box Expressed in T Cells Is a Mediator of Angiotensin II Induced Inflammation, Vascular Dysfunction and Oxidative Stress in the Murine Vasculature

Abstract

Recent studies described a protection from atherosclerosis by targeting of the Th1 key transcription factor T box expressed in T cells (T-bet). It remains to be established, whether T-bet is involved in mediating angiotensin II (ATII) induced vascular dysfunction and oxidative stress. ATII (1mg/kg/d) was administered by osmotic minipumps for one week and radiotelemetry was performed in T-bet-/- vs. control C57/BL6(WT) mice. Vascular dysfunction was assessed by isometric tension studies and reactive oxygen species (ROS) were detected by using DHE staining of aortic cryosections, aortic rings Lucigenin enhanced chemiluminescence (ECL) and L-012 enhanced blood oxidative burst. Protein expression was determined by western blot and mRNA expression by realtime PCR. CD4+ cytokines were measured by ELISA and myelomonocytic cells were analyzed by FACS and IHC. Aortic T-bet protein expression was increased in response to ATII in WT mice. In T-bet deficient mice AT II caused a similar increase of blood pressure as compared to WT. In contrast to WT, T-bet-/- showed an attenuated vascular dysfunction, ROS production and expression of NADPH oxidase subunits in response to AT II. Furthermore, iNOS mRNA expression and protein tyrosine nitration in the aorta was markedly reduced in T-bet-/- mice which showed a significant decrease of macrophages in the vascular wall caused by a reduced presence of pro-inflammatory cells after AT II treatment compared to WT. In a rescue experiment we transferred WT CD4+ T cells in T-bet deficient mice which resulted in increased vascular oxidative stress and dysfunction. We conclude, that T-bet mediates, at least in part, ATII induced vascular damage and might represent a novel target to treat vascular dysfunction and inflammation in arterial hypertension.