Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Br J Pharmacol. 2011 Jul;163(5):974-83. doi: 10.1111/j.1476-5381.2011.01295.x.
ApolipoproteinE-deficient [apoE (-/-)] mice, a model of human atherosclerosis, develop endothelial dysfunction caused by decreased levels of nitric oxide (NO). The endogenous peptide, angiotensin-(1-7) [Ang-(1-7)], acting through its specific GPCR, the Mas receptor, has endothelium-dependent vasodilator properties. Here we have investigated if chronic treatment with Ang-(1-7) improved endothelial dysfunction in apoE (-/-) mice.
ApoE (-/-) mice fed on a lipid-rich Western diet were divided into three groups and treated via osmotic minipumps with either saline, Ang-(1-7) (82 µg·kg(-1) ·h(-1) ) or the same dose of Ang-(1-7) together with D-Ala-Ang-(1-7) (125 µg·kg(-1) ·h(-1) ) for 6 weeks. Renal vascular function was assessed in isolated perfused kidneys.
Ang-(1-7)-treated apoE (-/-) mice showed improved renal endothelium-dependent vasorelaxation induced by carbachol and increased renal basal cGMP production, compared with untreated apoE (-/-) mice. Tempol, a reactive oxygen species (ROS) scavenger, improved endothelium-dependent vasorelaxation in kidneys of saline-treated apoE (-/-) mice whereas no effect was observed in Ang-(1-7)-treated mice. Chronic treatment with D-Ala-Ang-(1-7), a specific Mas receptor antagonist, abolished the beneficial effects of Ang-(1-7) on endothelium-dependent vasorelaxation. Renal endothelium-independent vasorelaxation showed no differences between treated and untreated mice. ROS production and expression levels of the NAD(P)H oxidase subunits gp91phox and p47phox were reduced in isolated preglomerular arterioles of Ang-(1-7)-treated mice, compared with untreated mice, whereas eNOS expression was increased.
Chronic infusion of Ang-(1-7) improved renal endothelial function via Mas receptors, in an experimental model of human cardiovascular disease, by increasing levels of endogenous NO.
载脂蛋白 E 缺陷型（apoE（-/-））小鼠，一种人类动脉粥样硬化的模型，由于一氧化氮（NO）水平降低而导致内皮功能障碍。内源性肽血管紧张素-(1-7) [Ang-(1-7)]通过其特定的 G 蛋白偶联受体 Mas 受体发挥作用，具有内皮依赖性血管舒张特性。在这里，我们研究了慢性 Ang-(1-7) 治疗是否改善了 apoE（-/-）小鼠的内皮功能障碍。
apoE（-/-）小鼠喂食富含脂质的西方饮食，分为三组，通过渗透微型泵分别用生理盐水、Ang-（1-7）（82μg·kg（-1）·h（-1））或相同剂量的 Ang-（1-7）和 D-Ala-Ang-（1-7）（125μg·kg（-1）·h（-1））治疗 6 周。在分离的灌注肾脏中评估肾血管功能。
与未治疗的 apoE（-/-）小鼠相比，Ang-（1-7）治疗的 apoE（-/-）小鼠表现出由卡巴胆碱诱导的肾内皮依赖性血管舒张增强，并且肾基础 cGMP 产生增加。ROS 清除剂 Tempol 改善了生理盐水治疗的 apoE（-/-）小鼠的内皮依赖性血管舒张，而 Ang-（1-7）治疗的小鼠则没有观察到这种作用。慢性给予 D-Ala-Ang-（1-7），一种特异性 Mas 受体拮抗剂，消除了 Ang-（1-7）对内皮依赖性血管舒张的有益作用。治疗和未治疗的小鼠之间肾内皮非依赖性血管舒张没有差异。与未治疗的小鼠相比，Ang-（1-7）治疗的小鼠的分离肾小球前小动脉中的 ROS 产生和 NAD（P）H 氧化酶亚基 gp91phox 和 p47phox 的表达水平降低，而 eNOS 表达增加。
在人类心血管疾病的实验模型中，慢性输注 Ang-（1-7）通过 Mas 受体增加内源性 NO 的水平，改善了肾内皮功能。
