Department of Pharmacology, University of Iowa, College of Medicine, 500 Newton Road, 340B EMRB, Iowa City, IA 52242, USA.
Stroke. 2012 Dec;43(12):3358-63. doi: 10.1161/STROKEAHA.112.667063. Epub 2012 Nov 15.
Angiotensin II produces oxidative stress and endothelial dysfunction in cerebral arteries, and angiotensin II type I receptors may play a role in longevity and vascular aging. Angiotensin-converting enzyme type 2 (ACE2) converts angiotensin II to angiotensin (1-7) and thus, may protect against effects of angiotensin II. We hypothesized that ACE2 deficiency increases oxidative stress and endothelial dysfunction in cerebral arteries and examined the role of ACE2 in age-related cerebrovascular dysfunction.
Endothelial function, expression of angiotensin system components, NADPH oxidase subunits, and proinflammatory cytokines were examined in cerebral arteries from adult (12 months old) and old (24 months old) ACE2 knockout (KO) and wild-type (WT) mice. The superoxide scavenger tempol was used to examine the role of oxidative stress on endothelial function.
Vasodilatation to acetylcholine was impaired in adult ACE2 KO (24±6% [mean±SE]) compared with WT mice (52±7%; P<0.05). In old mice, vasodilatation to acetylcholine was impaired in WT mice (29±6%) and severely impaired in ACE2 KO mice (7±5%). Tempol improved endothelial function in adult and old ACE2 KO and WT mice. Aging increased mRNA for tumor necrosis factor-α in WT mice, and significantly increased mRNA levels of NAPDH oxidase 2, p47(phox), and Regulator of calcineurin 1 in both ACE2 KO and WT mice. mRNA levels of angiotensin system components did not change during aging.
ACE2 deficiency impaired endothelial function in cerebral arteries from adult mice and augmented endothelial dysfunction during aging. Oxidative stress plays a critical role in cerebrovascular dysfunction induced by ACE2 deficiency and aging.
血管紧张素 II 可在脑动脉中产生氧化应激和内皮功能障碍，血管紧张素 II 型 1 型受体（angiotensin II type 1 receptor，AT1R）可能在长寿和血管老化中发挥作用。血管紧张素转换酶 2（angiotensin-converting enzyme 2，ACE2）可将血管紧张素 II 转化为血管紧张素（1-7），从而可能起到保护血管紧张素 II 作用。我们假设 ACE2 缺乏会增加脑动脉中的氧化应激和内皮功能障碍，并研究 ACE2 在与年龄相关的脑血管功能障碍中的作用。
我们检测了成年（12 月龄）和老年（24 月龄）ACE2 敲除（knockout，KO）和野生型（wild-type，WT）小鼠脑动脉中的内皮功能、血管紧张素系统成分的表达、NADPH 氧化酶亚基和促炎细胞因子，并使用超氧化物清除剂四乙噻吩（tempol）来研究氧化应激对内皮功能的作用。
与 WT 小鼠（52±7%）相比，成年 ACE2 KO 小鼠（24±6%）的乙酰胆碱引起的血管舒张受损（P<0.05）。在老年小鼠中，WT 小鼠的乙酰胆碱引起的血管舒张受损（29±6%），而 ACE2 KO 小鼠则严重受损（7±5%）。Tempol 改善了成年和老年 ACE2 KO 和 WT 小鼠的内皮功能。衰老使 WT 小鼠的肿瘤坏死因子-α mRNA 增加，并且使 ACE2 KO 和 WT 小鼠的 NADPH 氧化酶 2、p47(phox)和钙调神经磷酸酶调节因子 1 的 mRNA 水平显著增加。血管紧张素系统成分的 mRNA 水平在衰老过程中没有变化。
ACE2 缺乏会损害成年小鼠脑动脉的内皮功能，并加剧衰老过程中的内皮功能障碍。氧化应激在 ACE2 缺乏和衰老引起的脑血管功能障碍中起关键作用。
