大鼠和人类的慢性肝损伤会上调新型酶血管紧张素转换酶2。
Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2.
作者信息
Paizis G, Tikellis C, Cooper M E, Schembri J M, Lew R A, Smith A I, Shaw T, Warner F J, Zuilli A, Burrell L M, Angus P W
机构信息
University of Melbourne, Department of Medicine, Austin Health, Heidelberg, Victoria, Australia.
出版信息
Gut. 2005 Dec;54(12):1790-6. doi: 10.1136/gut.2004.062398. Epub 2005 Sep 15.
BACKGROUND
Angiotensin converting enzyme (ACE) 2 is a recently identified homologue of ACE that may counterregulate the actions of angiotensin (Ang) II by facilitating its breakdown to Ang 1-7. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of cirrhosis but the role of ACE2 in liver disease is not known.
AIMS
This study examined the effects of liver injury on ACE2 expression and activity in experimental hepatic fibrosis and human cirrhosis, and the effects of Ang 1-7 on vascular tone in cirrhotic rat aorta.
METHODS
In sham operated and bile duct ligated (BDL) rats, quantitative reverse transcriptase-polymerase chain reaction was used to assess hepatic ACE2 mRNA, and western blotting and immunohistochemistry to quantify and localise ACE2 protein. ACE2 activity was quantified by quenched fluorescent substrate assay. Similar studies were performed in normal human liver and in hepatitis C cirrhosis.
RESULTS
ACE2 mRNA was detectable at low levels in rat liver and increased following BDL (363-fold; p < 0.01). ACE2 protein increased after BDL (23.5-fold; p < 0.05) as did ACE2 activity (fourfold; p < 0.05). In human cirrhotic liver, gene (>30-fold), protein expression (97-fold), and activity of ACE2 (2.4 fold) were increased compared with controls (all p < 0.01). In healthy livers, ACE2 was confined to endothelial cells, occasional bile ducts, and perivenular hepatocytes but in both BDL and human cirrhosis there was widespread parenchymal expression of ACE2 protein. Exposure of cultured human hepatocytes to hypoxia led to increased ACE2 expression. In preconstricted rat aorta, Ang 1-7 alone did not affect vascular tone but it significantly enhanced acetylcholine mediated vasodilatation in cirrhotic vessels.
CONCLUSIONS
ACE2 expression is significantly increased in liver injury in both humans and rat, possibly in response to increasing hepatocellular hypoxia, and may modulate RAS activity in cirrhosis.
背景
血管紧张素转换酶（ACE）2是最近发现的ACE同源物，它可能通过促进血管紧张素（Ang）II分解为Ang 1-7来对抗其作用。肾素-血管紧张素系统（RAS）与肝硬化的发病机制有关，但ACE2在肝病中的作用尚不清楚。
目的
本研究探讨肝损伤对实验性肝纤维化和人类肝硬化中ACE2表达及活性的影响，以及Ang 1-7对肝硬化大鼠主动脉血管张力的影响。
方法
在假手术和胆管结扎（BDL）大鼠中，采用定量逆转录聚合酶链反应评估肝脏ACE2 mRNA，采用蛋白质印迹法和免疫组织化学法定量和定位ACE2蛋白。通过淬灭荧光底物法对ACE2活性进行定量。在正常人肝脏和丙型肝炎肝硬化中进行了类似研究。
结果
ACE2 mRNA在大鼠肝脏中低水平可检测到，BDL后增加（363倍；p < 0.01）。BDL后ACE2蛋白增加（23.5倍；p < 0.05），ACE2活性也增加（4倍；p < 0.05）。与对照组相比，人类肝硬化肝脏中ACE2基因（>30倍）、蛋白表达（97倍）和活性（2.4倍）均增加（均p < 0.01）。在健康肝脏中，ACE2局限于内皮细胞、偶尔的胆管和中央静脉周围的肝细胞，但在BDL和人类肝硬化中，ACE2蛋白均在实质细胞中广泛表达。培养的人肝细胞暴露于缺氧环境会导致ACE2表达增加。在预先收缩的大鼠主动脉中，单独的Ang 1-7不影响血管张力，但它显著增强了乙酰胆碱介导的肝硬化血管舒张。
结论
在人类和大鼠的肝损伤中，ACE2表达均显著增加，可能是对肝细胞缺氧增加的反应，并可能调节肝硬化中的RAS活性。
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