Stroke：ACE2缺乏和氧化应激在老龄脑血管功能障碍中发挥了重要作用

血管紧张素II产生氧化应激和脑动脉内皮功能不全，血管紧张素II的I型受体可能在寿命及血管衰老中起到作用。血管紧张素转化酶2型（ACE2）将血管紧张素II转化为血管紧张素（1-7），并可对血管紧张素II的效应起保护作用。美国爱荷华州大学的Ricardo A. Pena Silva博士等人通过研究发现：ACE2缺乏损害成年鼠脑动脉内皮功能，加剧了衰老过程中内皮功能的损害。氧化应激在ACE2缺乏和衰老诱发的脑血管功能障碍中起到了重要的作用。相关论文发表在Stroke杂志2012年11月15日在线版上。

研究人员分别在ACE2基因敲除（KO）和野生型（WT）的成年鼠（12个月）、老年鼠（24个月）的脑动脉中检测内皮功能、血管紧张素系统成分的表达、NADPH氧化酶亚单位和促炎细胞因子。使用超氧化物清道夫tempol检验氧化应激对内皮功能的作用。

结果发现：ACE2基因敲除型鼠对乙酰胆碱产生的血管扩张作用(24±6%)相较野生型鼠(52±7%)显着受损（P<0.05）。WT老年鼠对乙酰胆碱的血管扩张作用受损(29±6%)，在ACE2 KO老年鼠显着受损(7±5%)。Tempol改善成年和老年ACE2 KO和MT鼠的内皮功能。衰老增加了WT鼠肿瘤坏死因子α mRNA的表达。ACE2 KO和WT鼠中都出现了NAPDH氧化酶、p47phox和钙调神经磷酸酶1的mRNA水平都显着增加。衰老过程中血管紧张素系统成分的mRNA水平没有发生改变。

研究人员得出结论：ACE2缺乏损害成年鼠脑动脉内皮功能，加剧了衰老过程中内皮功能的损害。氧化应激在ACE2缺乏和衰老诱发的脑血管功能障碍中起到了重要的作用。

doi: 10.1161/​STROKEAHA.112.667063
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Impact of ACE2 Deficiency and Oxidative Stress on Cerebrovascular Function With Aging

Ricardo A. Peña-Silva, MD, PhD, Yi Chu, PhD, Jordan D. Miller, PhD, Ian J. Mitchell, BSc, Josef M. Penninger, MD, Frank M. Faraci, PhD and Donald D. Heistad, MD

Background and Purpose—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. Methods—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. Results—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, p47phox, and Regulator of calcineurin 1 in both ACE2 KO and WT mice. mRNA levels of angiotensin system components did not change during aging. Conclusions—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.