Chrissobolis Sophocles, Drummond Grant R, Faraci Frank M, Sobey Christopher G
aVascular Biology & Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, Australia bDepartments of Internal Medicine and Pharmacology, Cardiovascular Center, The University of Iowa Carver College of Medicine cIowa City Veterans Affairs Healthcare System, Iowa City, Iowa, USA.
J Hypertens. 2014 Sep;32(9):1815-21. doi: 10.1097/HJH.0000000000000259.
An elevated plasma aldosterone level is an independent cardiovascular risk factor. Although excess aldosterone promotes cardiovascular disease, no studies have examined the effect of increased plasma aldosterone on the cerebral circulation. A major source of vascular reactive oxygen species (ROS) during cardiovascular disease is the NADPH oxidases. Because Nox2-containing NADPH oxidase (Nox2 oxidase) is highly expressed in the cerebral endothelium, we postulated that it might contribute to ROS generation and vascular dysfunction in response to aldosterone. Here, we examined the effect of aldosterone and Nox2 oxidase on ROS production and endothelial dysfunction in the cerebral circulation, and whether the effects of aldosterone are exacerbated in aged mice.
In adult (average age ∼24-25 weeks) wild-type and Nox2-deficient (Nox2(/y)) mice, neither vehicle nor aldosterone (0.28 mg/kg per day for 14 days) affected blood pressure (measured using tail-cuff). By contrast, aldosterone treatment reduced dilation of the basilar artery (measured using myography) to the endothelium-dependent agonist acetylcholine in wild-type mice (P < 0.05), but had no such effect in Nox2(/y) mice (P > 0.05). Aldosterone increased basal and phorbol dibutyrate-stimulated superoxide production (measured using L-012-enhanced chemiluminesence) in cerebral arteries from wild-type but not from Nox2(/y) mice. In aged wild-type mice (average age ∼70 weeks), aldosterone treatment increased blood pressure, but had a similar effect on cerebral artery superoxide levels as in adult wild-type mice.
These data indicate that Nox2 oxidase mediates aldosterone-induced increases in ROS production and endothelial dysfunction in cerebral arteries from adult mice independently of blood pressure changes. Aldosterone-induced hypertension is augmented during aging.
血浆醛固酮水平升高是一个独立的心血管危险因素。尽管醛固酮过多会促进心血管疾病，但尚无研究探讨血浆醛固酮升高对脑循环的影响。心血管疾病期间血管活性氧（ROS）的一个主要来源是NADPH氧化酶。由于含Nox2的NADPH氧化酶（Nox2氧化酶）在脑内皮中高度表达，我们推测它可能在醛固酮作用下导致ROS生成和血管功能障碍。在此，我们研究了醛固酮和Nox2氧化酶对脑循环中ROS产生和内皮功能障碍的影响，以及醛固酮的作用在老年小鼠中是否会加剧。
在成年（平均年龄约24 - 25周）野生型和Nox2基因缺陷（Nox2(/y)）小鼠中，无论是溶剂对照还是醛固酮（0.28毫克/千克/天，持续14天）均不影响血压（采用尾套法测量）。相比之下，醛固酮处理使野生型小鼠基底动脉对内皮依赖性激动剂乙酰胆碱的扩张（采用肌动描记法测量）减弱（P < 0.05），但对Nox2(/y)小鼠无此作用（P > 0.05）。醛固酮增加了野生型小鼠脑动脉基础状态下以及佛波酯刺激后的超氧化物生成（采用L - 012增强化学发光法测量），而Nox2(/y)小鼠脑动脉则未出现此现象。在老年野生型小鼠（平均年龄约70周）中，醛固酮处理使血压升高，但对脑动脉超氧化物水平的影响与成年野生型小鼠相似。
这些数据表明，Nox2氧化酶介导醛固酮诱导的成年小鼠脑动脉ROS生成增加和内皮功能障碍，且与血压变化无关。醛固酮诱导的高血压在衰老过程中会加剧。
