Widder Julian D, Fraccarollo Daniela, Galuppo Paolo, Hansen Jason M, Jones Dean P, Ertl Georg, Bauersachs Johann
Medizinische Klinik I, Universitätsklinikum, Josef-Schneider-Str 2, 97080 Würzburg, Germany.
Hypertension. 2009 Aug;54(2):338-44. doi: 10.1161/HYPERTENSIONAHA.108.127928. Epub 2009 Jun 8.
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 > or =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.
在高血压期间以及对血管紧张素II的反应中，心血管系统中的活性氧会增加。由于线粒体参与活性氧的生成，我们试图研究硫氧还蛋白2（一种线粒体特异性抗氧化酶）的作用。构建了过表达人硫氧还蛋白2的小鼠（Tg(hTrx2)小鼠），并与C57BL/6J小鼠回交≥6代。使用渗透微型泵，通过输注血管紧张素II（每分钟400 ng/kg）持续14天，使12周龄的雄性Tg(hTrx2)小鼠或同窝野生型小鼠患高血压。在基线条件下，Tg(hTrx2)小鼠和野生型动物的收缩期动脉血压无差异（分别为101±1和102±1 mmHg）。血管紧张素II诱导的野生型小鼠高血压（145±2 mmHg）在Tg(hTrx2)小鼠中显著减轻（124±1 mmHg；P<0.001）。血管紧张素II输注后，野生型小鼠的主动脉内皮依赖性舒张功能显著降低，但转基因小鼠几乎未改变。在Tg(hTrx2)小鼠中，血管紧张素II输注后升高的血管超氧化物和过氧化氢水平以及NADPH氧化酶亚基的表达均显著减弱。血管紧张素II输注后，野生型小鼠的线粒体超氧阴离子水平升高，而在Tg(hTrx2)小鼠中这种升高受到抑制。血管紧张素II输注显著增加了野生型小鼠而非Tg(hTrx2)小鼠的心肌超氧化物形成、心脏重量和心肌细胞大小。这些数据表明线粒体硫氧还蛋白2在慢性血管紧张素II输注期间心血管改变和高血压的发生中起主要作用。硫氧还蛋白2可能是预防和治疗高血压及氧化应激的重要治疗靶点。
