Attenuation of Angiotensin II-Induced Vascular Dysfunction and Hypertension by Overexpression of Thioredoxin 2

作者：Widder Julian D^*; Fraccarollo Daniela; Galuppo Paolo; Hansen Jason M; Jones Dean P; Ertl Georg; Bauersachs Johann

来源：Hypertension, 2009, 54(2): 338-344.

DOI：10.1161/HYPERTENSIONAHA.108.127928

• angiotensin II
• endothelial function
• hypertension
• mitochondria
• thioredoxin 2
• reactive oxygen species

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 (Tg(hTrx2) mice) and backcrossed to C57BL/6J mice for >= 6 generations. Twelve-week-old male Tg(hTrx2) 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 Tg(hTrx2) 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 Tg(hTrx2) 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 Tg(hTrx2) mice. Mitochondrial superoxide anion levels were augmented after angiotensin II infusion in wild-type mice, and this was blunted in Tg(hTrx2) mice. Angiotensin II infusion significantly increased myocardial superoxide formation, heart weight, and cardiomyocyte size in wild-type but not in Tg(hTrx2) 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. (Hypertension. 2009; 54: 338-344.)

• 出版日期2009-8