Abstract 1758: Attenuation of Angiotensin II induced Hypertension, Vascular Dysfunction and Cardiomyocyte Hypertrophy by Overexpression of Thioredoxin-2
Reactive oxygen species (ROS) increase in the cardiovascular system during hypertension and in response to angiotensin II. As mitochondria contribute to ROS-generation we sought to investigate the role of thioredoxin 2, a mitochondria specific antioxidant enzyme. Mice were created with overexpression of human thioredoxin-2 (TghTrx2-mice) driven by a CAG promoter and backcrossed to C57/bl6J mice for at least 6 generations. 12 week old male TghTrx2-mice or littermate wild type (WT) mice were made hypertensive by infusion of angiotensin II (400 ng/kg/min) for 14 days using osmotic minipumps. Systolic arterial blood pressure was not different between TghTrx2 and littermate animals under baseline conditions (101 ± 1 resp. 102 ± 1 mmHg n = 6). The angiotensin II induced increase in mean arterial blood pressure in WT (145 ± 2 mmHg n = 6) was significantly attenuated in TghTrx2-mice (124 ± 1 mmHg, p < 0.05 n = 6). Endothelium-dependent relaxation induced by acetylcholine in PGF2α-preconstricted aortic rings was significantly reduced in WT following angiotensin II infusion, but nearly unchanged in TghTrx2. Superoxide production, measured by monitoring the formation of 2-hydroxyethidium from dihydroethidum by HPLC, significantly increased in aortae from WT mice, but not from TghTrx2-mice receiving angiotensin II infusion. Furthermore, cardiomyocyte diameter was significantly increased in WT mice after angiotensin II infusion this was blunted in TghTrx2-mice. These data indicate a major role for thioredoxin 2 in the development of vascular dysfunction and hypertension during chronic angiotensin II infusion. Thioredoxin 2 may represent an important therapeutic target in treatment of hypertension and oxidative stress.