Abstract 18310: The Th1 Transcription Factor T Box Expressed in T Cells (T-bet) mediates Angiotensin II Induced Vascular Dysfunction and Oxidative Stress
Background: Recent studies have shown a protection from atherosclerosis by genetical knockout of the Th1 key transcription factor T box expressed in T cells (T-bet) in apoE−/− mice. Whether T-bet is involved in mediating angiotenin II (ATII) induced vascular dysfunction and oxidative stress is unknown.
Methods and results: After 1 week of ATII treatment (1mg/kg/d, administered by osmotic minipumps), T-bet deficient mice (T-bet KO) showed ameliorated endothelial and smooth muscle dysfunction (assessed by isometric tension studies in isolated aortic rings) as compared to wild type littermates (WT), which showed an increased expression of T-bet protein (as assessed by western blot) in aortic tissue. Likewise, dihydroethidine staining of aortic cryosections revealed a reduced ROS-signal in all layers of the vascular wall, and whole blood respiratory burst and cardiac NADPH oxidase activtity measured by L0-12 and lucigenin enhanced chemiluminescence was blunted in ATII-treated T-bet KO, as well as protein tyrosin nitration. Increased levels of Th2 cytokines released by isolated splenic CD4+ T cells measured by ELISA were paralleled by blunted IFN-gamma production in ATII treated T-bet KO as compared to WT. In addition, FoxP3 protein expression and Il-10 formation was strongly induced in spleens of T-bet KO, underlining the anti-inflammatory phenotype of these mice in this experimental model of vascular dysfunction.
Conclusions: T-bet deficiency protects from ATII induced vascular dysfunction and oxidative stress by switching a proinflammatory Th1 to a Th2 and Treg T cell phenotype. We conclude, that T-bet mediates, at least in part, ATII induced vascular damage and might represent a novel target to treat both atherosclerosis and arterial hypertension.
- © 2010 by American Heart Association, Inc.