Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, China.
Antioxid Redox Signal. 2010 Sep 15;13(6):757-68. doi: 10.1089/ars.2009.2831.
The mechanisms underlying the effect of the renin-angiotensin-aldosterone system (RAAS) inhibition on endothelial dysfunction in type 2 diabetes are incompletely understood. This study explored a causal relationship between RAAS activation and oxidative stress involved in diabetes-associated endothelial dysfunction. Daily oral administration of valsartan or enalapril at 10 mg/kg/day to db/db mice for 6 weeks reversed the blunted acetylcholine-induced endothelium-dependent dilatations, suppressed the upregulated expression of angiotensin II type 1 receptor (AT(1)R) and NAD(P)H oxidase subunits (p22(phox) and p47(phox)), and reduced reactive oxygen species (ROS) production. Acute exposure to AT(1)R blocker losartan restored the impaired endothelium-dependent dilatations in aortas of db/db mice and also in renal arteries of diabetic patients (fasting plasma glucose level > or =7.0 mmol/l). Similar observations were also made with apocynin, diphenyliodonium, or tempol treatment in db/db mouse aortas. DHE fluorescence revealed an overproduction of ROS in db/db aortas which was sensitive to inhibition by losartan or ROS scavengers. Losartan also prevented the impairment of endothelium-dependent dilatations under hyperglycemic conditions that were accompanied by high ROS production. The present study has identified an initiative role of AT(1)R activation in mediating endothelial dysfunction of arteries from db/db mice and diabetic patients.
肾素-血管紧张素-醛固酮系统（RAAS）抑制对 2 型糖尿病内皮功能障碍的作用机制尚不完全清楚。本研究探讨了 RAAS 激活与糖尿病相关内皮功能障碍中涉及的氧化应激之间的因果关系。10mg/kg/天的缬沙坦或依那普利每天口服给予 db/db 小鼠 6 周，可逆转乙酰胆碱诱导的内皮依赖性舒张功能减弱，抑制血管紧张素 II 型 1 型受体（AT(1)R）和 NAD(P)H 氧化酶亚基（p22(phox)和 p47(phox)）的上调表达，并减少活性氧（ROS）的产生。急性给予 AT(1)R 阻滞剂洛沙坦可恢复 db/db 小鼠主动脉中受损的内皮依赖性舒张功能，也可恢复糖尿病患者（空腹血糖水平≥7.0mmol/l）的肾动脉内皮依赖性舒张功能。用 apocynin、diphenyliodonium 或 tempol 处理 db/db 小鼠的主动脉也观察到类似的结果。DHE 荧光显示 db/db 主动脉中 ROS 过度产生，洛沙坦或 ROS 清除剂可抑制其产生。洛沙坦还可防止高血糖条件下内皮依赖性舒张功能受损，此时伴有高 ROS 产生。本研究确定了 AT(1)R 激活在介导 db/db 小鼠和糖尿病患者动脉内皮功能障碍中的主动作用。
