Published online before print June 8, 2009, doi: 10.1161/HYPERTENSIONAHA.108.127928
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(Hypertension. 2009;54:338.)
© 2009 American Heart Association, Inc.
Original Articles |
Attenuation of Angiotensin II–Induced Vascular Dysfunction and Hypertension by Overexpression of Thioredoxin 2
From the Department of Internal Medicine I (J.D.W., D.F., P.G., G.E., J.B.), University of Würzburg, Würzburg, Germany; and the Division of Pulmonology, Allergy, Cystic Fibrosis, and Sleep, Department of Pediatrics (J.M.H.), and Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine (D.P.J.), Emory University, Atlanta, Georgia.
Correspondence to Julian D. Widder, Medizinische Klinik I, Universitätsklinikum, Josef-Schneider-Str 2, 97080 Würzburg, Germany. E-mail widder_j{at}medizin.uni-wuerzburg.de
Reactive oxygen species increase in the cardiovascular system during hypertension and in response to angiotensin II. Because mitochondria contribute to reactive oxygen species 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) and backcrossed to C57BL/6J mice for 
6 generations. Twelve-week-old male TghTrx2 or littermate wild-type mice were made hypertensive by infusion of angiotensin II (400 ng/kg per minute) for 14 days using osmotic minipumps. Systolic arterial blood pressure was not different between TghTrx2 and wild-type animals under baseline conditions (101±1 respective 102±1 mm Hg). The angiotensin II–induced hypertension in wild-type mice (145±2 mm Hg) was significantly attenuated in TghTrx2 mice (124±1 mm Hg; P<0.001). Aortic endothelium-dependent relaxation was significantly reduced in wild-type mice after angiotensin II infusion but nearly unchanged in transgenic mice. Elevated vascular superoxide and hydrogen peroxide levels, as well as expression of NADPH oxidase subunits in response to angiotensin II infusion, were significantly attenuated in TghTrx2 mice. Mitochondrial superoxide anion levels were augmented after angiotensin II infusion in wild-type mice, and this was blunted in TghTrx2 mice. Angiotensin II infusion significantly increased myocardial superoxide formation, heart weight, and cardiomyocyte size in wild-type but not in TghTrx2 mice. These data indicate a major role for mitochondrial thioredoxin 2 in the development of cardiovascular alterations and hypertension during chronic angiotensin II infusion. Thioredoxin 2 may represent an important therapeutic target for the prevention and treatment of hypertension and oxidative stress.
Key Words: angiotensin II • endothelial function • hypertension • mitochondria • thioredoxin 2 • reactive oxygen species
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Hypertension 2009 54: 224-225.
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  T. Fukai Mitochondrial Thioredoxin: Novel Regulator for NADPH Oxidase and Angiotensin II-Induced Hypertension Hypertension, August 1, 2009; 54(2): 224 - 225. [Full Text] [PDF]
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