血管紧张素转换酶2-血管紧张素1-7-Mas轴对血管作用的研究进展

血管紧张素转换酶2（ACE2）和Mas受体的发现使人们对肾素-血管紧张素（RAS）有了更全面的认识。ACE2可水解血管紧张素Ⅰ和血管紧张素Ⅱ直接或间接生成血管紧张素1-7（Ang 1-7）,并与高血压的形成密切相关。Ang 1-7主要通过Mas受体引起血管舒张、抑制细胞增殖。ACE2-Ang1-7-Mas轴的发现为RAS的研究、高血压等心血管疾病的防治和新药开发提供了新的思路和方向。     

肾素-血管紧张素系统的新调节分子:ACE2

血管紧张素转化酶（angiotensin—converting enzyme,ACE）为含锌的金属蛋白酶,是肾素-血管紧张素系统（renin—angiotensin system,RAS）重要的调节分子。血管紧张素转化酶2（angiotensin—con—verting enzyme2,ACE2）是迄今发现的唯一的ACE同系物（homologue）,它主要分布于睾丸、肾脏和心脏。ACE2可水解血管紧张素Ⅰ（angiotensinⅠ,AngⅠ）和血管紧张素Ⅱ（angiotensinⅡ,AngⅡ）羧基端的1个氨基酸残基,分别形成Ang1-9和有血管舒张作用的Ang1-7。ACE2的生理病理作用还不甚明了,传统的ACE抑制剂不能抑制ACE2的活性。ACE2在心血管、肾脏系统的作用可能与ACE相反．与ACE共同调节心脏、肾脏等脏器的正常功能。     

肠淋巴液引流对失血性休克小鼠心肌组织ACE/ACE2的作用

目的：观察失血性休克后小鼠心肌组织血管紧张素转换酶（ACE）/ACE2平衡的变化及肠淋巴液引流（PHSML）的作用。方法：BALB/c雄性小鼠24只,随机分为对照组、假手术组、休克组、休克+引流组（n=6）。建立失血性休克模型,行液体复苏;休克+引流组液体复苏后,引流肠淋巴液。在液体复苏后6 h或假手术组相应时间点、对照组于麻醉后,留取心肌组织,qRT-PCR法检测ACE、ACE2、血管紧张素Ⅱ （Ang Ⅱ）1型受体（AT1R）、Mas相关G蛋白偶联受体（Mas1R）的mRNA表达,ELISA方法检测Ang Ⅱ和Ang （1-7）含量。结果：休克组小鼠心肌组织ACE与AT1R mRNA表达、Ang Ⅱ水平均显著高于对照组与假手术组,ACE2与Mas1R mRNA表达显著低于对照组与假手术组、Ang （1-7）含量显著低于对照组,ACE/ACE2、Ang Ⅱ/Ang （1-7）、AT1R/Mas1R显著高于对照组与假手术组;PHSML引流显著抑制了失血性休克对这些指标的作用。结论：失血性休克上调心肌ACE-Ang Ⅱ-AT1R轴、下调ACE2-Ang （1-7）-Mas1R轴表达,引起ACE/ACE2失衡;PHSML引流下调ACE-Ang Ⅱ-AT1R轴、上调ACE2-Ang （1-7）-Mas1R轴表达,在一定程度上维持了ACE/ACE2平衡。     

肾脏中肾素-血管紧张素系统的生理和病理生理作用

肾脏中肾素-血管紧张素系统(RAS)在肾脏生理功能的调节中有重要作用.近年来,肾脏RAS的新成分及新作用机制不断被发现.转基因动物研究使肾脏血管紧张素Ⅱ(AngⅡ)在血压及水钠平衡调节中的作用进一步阐明;AngⅡ的非血流动力学作用已经确立;血管紧张素转换酶2(ACE2)及Ang 1～7对肾功能的调节作用也已得到认可.肾素/前肾素特异性受体、ACE的信号转导功能,以及AT1受体的转激活功能等,已成为肾脏生理科学研究的热点.这些研究对于人们认识肾脏局部RAS功能,探讨延缓慢性肾脏病的进展的治疗策略具有重要意义.     

血管紧张素转换酶2对心脏作用的研究进展

血管紧张素转换酶2作为肾素—血管紧张素系统的新成员,对心脏功能及心脏节律发挥着重要的调节作用。缺乏ACE2会造成心功能的下降,原因可能是心肌慢性缺氧、血管紧张素Ⅱ水平的提高、血管紧张素(1-7)对心脏保护作用的缺失以及其他肽类底物的增加。但同时ACE2的过度表达又会引起心脏传导紊乱和致死性的心律失常。因此,ACE2精确的生理作用有待进一步明确,但调节ACE2的活性可能为心血管疾病的治疗提出了新的思路。本文主要介绍了ACE2的分布与特性,及其对心功能及心脏节律的影响。     

作为肾素-血管紧张素系统调节器和SARS病毒受体的人血管紧张素转换酶2

人血管紧张素转换酶2(ACE2)是目前已知的惟一的人血管紧张素转换酶(ACE)的同源物,是一种新型的金属羧肽酶,很多特性与ACE截然不同.ACE2在肾素-血管紧张素系统(RAS)中具有独特的作用,调节心脏功能和机体血压.最近ACE2被鉴定为SARS病毒的功能受体.ACE2已经成为目前药物研发的新靶点.对ACE2的认识才刚刚开始,有待进-步深入研究.     

闭锁卵泡中肾素—血管紧张素质系统的变化

目的：探讨卵巢局部的肾素－血管紧张素系统（RAS）在卵泡闭锁中的作用。方法：应用卵巢细胞双室培养,放射免疫测定（RIA）及免疫组化方法研究猪卵巢的健康卵泡和闭锁卵泡的颗粒细胞和卵泡内膜细胞与RAS的关系;观察了血管紧张素Ⅱ（AngⅡ)拮抗剂Saralasin及血管紧张素转换酶（ACE）抑制剂Captopril的作用。结果（1）与健康卵泡相比较,闭锁卵泡的卵泡液及卵泡内膜细胞培养液中的AngⅡ浓度明显升高,肾素浓度则明显降低;而颗粒细胞培养液中的AngⅡ和肾素浓度均无明显改变;（2）闭锁卵泡切片的AngⅡ,2型血管紧张素Ⅱ受体（AT2）染色明显强于健康卵泡;AngⅡ和AT2水平在双室培养的闭锁卵泡的卵泡内膜细胞中明显强于健康卵泡的卵泡内膜细胞;健康和闭锁卵泡的颗粒细胞中的AngⅡ,AT2水平变化不大;（3）双室培养中加入Saralasin或Captopril培养48h后,（a)与健康卵泡相比,闭锁卵泡的卵泡内膜细胞培养液中的AngⅡ浓度显降低,肾素浓度明显升高;（b)健康和闭锁卵泡的卵泡内膜细胞AngⅡ和AT2免疫组化染色均呈现下降,（c)RIA结果显示,健康和闭锁卵泡的颗粒细胞培养液中的AngⅡ和肾素浓度无明显变化;免疫组化结果显示,颗粒细胞的AngⅡ,AT2水平亦无显改变。结论：卵泡闭锁与卵巢RAS密切相关,AngⅡ和AT2是卵泡闭锁的重要相关因子;卵泡闭锁过程中卵巢局部的RAS变化主要发生在卵泡内膜细胞;Saralasin和Captopril可能通过调节卵巢RAS而具有抑制卵泡闭锁的作用。     

血管紧张素转换酶2在心血管疾病中的调控作用

血管紧张素转换酶2(angiotensin-converting enzyme 2,ACE2)是肾素-血管紧张素系统(renin-angio-tensin system,RAS)的重要成员,广泛分布于肺、心血管系统、肠道、肾脏、中枢神经系统和脂肪组织中.ACE2具有多种生理功能,在防止高血压、动脉粥样硬化、心力衰竭、肺...     

血管紧张素转换酶2的功能和应用

人血管紧张素转换酶2（ACE2）是肾素-血管紧张素系统（RAS）的重要调节分子,它在控制心血管和血压的正常生理活动中具有重要的作用。此外,ACE2作为SARS病毒的受体,对于病毒的入侵起关键作用。目前ACE2已经被用于高血压和心血管相关疾病的药物靶标设计和基因治疗,随着研究的深入,ACE2在临床上的应用将更加广泛。     

自发性高血压大鼠心脏中ACE,AT1R,ACE2和MasR表达变化的研究

目的：通过观察血管紧张素转化酶（ACE）和血管紧张素转化酶2（ACE2）在Wistar-京都种大鼠（WKY）和自发性高血压（SHR）大鼠心脏组织中表达的差异,探讨ACE与ACE2在自发性高血压大鼠高血压形成中的作用。方法：自由饲喂14周龄WKY和SHR雄性大鼠一周后,用BSN-II多通道无创测压系统测定大鼠收缩压（SBP）、舒张压（DBP）、心率（HR）并称重;放免法测定血浆中血管血管紧张素Ⅱ（AngII）含量;Real-time PCR测定心脏组织中ACE,ATI受体（ATIR）,ACE2和Mas受体（MasR）mRNA的表达水平;Western blot法检测心脏组织中ACE2的蛋白表达。结果：SHR大鼠SBP和DBP均显著高于WKY大鼠（P〈0.01）;两组大鼠心率和体重无显著差异（P〉0.05）;SHR大鼠血浆中AngII含量显著升高（P〈0.05）;与WKY大鼠相比,SHR大鼠心脏中ACE mRNA表达均显著升高（P〈0.05）,ACE2的mRNA和蛋白表达水平均显著下降（P〈0.05）;心脏组织中AT1R和MasR的mRNA表达没有显著性变化（P〉0.05）。结论：ACE与ACE2表达失调是SHR大鼠高血压形成的主要原因之一,其机理可能与局部组织RAS系统ACE-AngII-AT1R通路过度活跃,ACE2-Ang（1-7）-MasR通路相对不足有关。     

Purification and characterization of angiotensin converting enzyme 2 (ACE2) from murine model of mesangial cell in culture

Angiotensin converting enzyme 2 (ACE2) is a component of the renin-angiotensin system (RAS) which converts Ang II, a potent vasoconstrictor peptide into Ang 1-7, a vasodilator peptide which may act as a negative feedback hormone to the actions of Ang II. The discovery of this enzyme added a new level of complexity to this system. The mesangial cells (MC) have multiple functions in glomerular physiology and pathophysiology and are able to express all components of the RAS. Despite of being localized in these cells, ACE2 has not yet been purified or characterized. In this study ACE2 from mice immortalized MC (IMC) was purified by ion-exchange chromatography. The purified enzyme was identified as a single band around 60-70 kDa on SDS-polyacrylamide gel and by Western blotting using a specific antibody. The optima pH and chloride concentrations were 7.5 and 200 mM, respectively. The N-terminal sequence was homologous with many species ACE2 N-terminal sequences as described in the literature. ACE2 purified from IMC was able to hydrolyze Ang II into Ang 1-7 and the K_m value for Ang II was determined to be 2.87 ± 0.76 μM. In conclusion, we purified and localized, for the first time, ACE2 in MC, which was able to generate Ang 1-7 from Ang II. Ang 1-7 production associated to Ang II degradation by ACE2 may exert a protective effect in the renal hemodynamic.     

Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases

Introduction  

Angiotensin-converting enzyme (ACE) 2, a homolog of ACE, converts angiotensin (Ang) II into Ang(1-7), and the vasoprotective effects of Ang(1-7) have been documented. We explored the hypothesis that serum autoantibodies to ACE2 predispose patients with connective tissue diseases to constrictive vasculopathy, pulmonary arterial hypertension (PAH), or persistent digital ischemia.     

白藜芦醇对AngⅡ诱导的血管平滑肌细胞CaN的影响

目的：观察白藜芦醇（Res）对血管紧张素Ⅱ（AngⅡ）诱导的血管平滑肌细胞（VSMCs）增殖及细胞中钙调蛋白（CaM）和钙调神经磷酸酶（CaN）活性的影响,并探讨其机制。方法：体外培养兔主动脉VSMCs,用免疫细胞化学方法鉴定。建立AngⅡ诱导的VSMCs增殖模型。取生长良好的第4～8代VSMCs,随机分为对照组,AnsⅡ组（0．1μmol／L）,AngⅡ＋Res组（20,40,80,160）μmol／L。应用MTT法检测细胞增殖程度,考马斯亮兰法进行CaM定量,定磷法进行CaN活性测定。结果：成功培养兔VSMCs并传代,免疫细胞化学染色均呈阳性表达。AngⅡ组VSMCs的增殖程度、CaM和CaN活性较对照组增高（P〈0．05,P〈0．01）。AngⅡ＋Res组各组VSMCs的CaM和CaN活性较AngⅡ组显著下降（P〈0．01）。结论：在一定范围内,Res可降低AngⅡ诱导的VSMCs增殖程度,其机制可能与干预CaN依赖的信号转导途径有关。     

肾上腺髓质素2的降压作用及其机制

目的:研究肾上腺髓质素2(ADM2)拮抗血管紧张素Ⅱ(AngⅡ)发挥舒张血管的作用及机制。方法:将18只180~200 g雄性SD大鼠随机分为3组(n=6):对照组、AngⅡ(150 ng/(kg·min))组和AngⅡ(150 ng/(kg·min))+ADM2(500 ng/(kg·h))组,采用皮下埋植微量渗透泵的方法给药。2周后颈动脉插管法测量大鼠血压,测定血浆一氧化氮(NO)含量和内皮型一氧化氮合酶(eNOS)活性。DHE染色法检测大鼠动脉壁活性氧产生。制备大鼠离体血管环,观察ADM2的舒血管作用。培养人脐静脉内皮细胞系EA.hy 926,用DCFH-DA荧光探针检测AngⅡ和ADM2对血管内皮细胞活性氧释放的影响。结果:与AngⅡ组相比,ADM2显著降低了大鼠血压,血浆中eNOS活性提高、NO含量增加,血管壁活性氧产生减少。ADM2呈浓度依赖性和内皮依赖性舒张血管环,并明显抑制了AngⅡ引起的血管内皮细胞活性氧产生。结论:ADM2可能通过拮抗AngⅡ诱导的血管内皮氧化应激效应,改善内皮功能,发挥舒张血管、降低血压的作用。     

ACE2 – From the renin–angiotensin system to gut microbiota and malnutrition

The renin–angiotensin system (RAS) is a complex network that regulates blood pressure, electrolyte and fluid homeostasis, as well as the function of several organs. Angiotensin-converting enzyme 2 (ACE2) was identified as an enzyme that negatively regulates the RAS by converting Ang II, the main bioactive molecule of the RAS, to Ang 1–7. Thus, ACE2 counteracts the role of angiotensin-converting enzyme (ACE) which generates Ang II from Ang I. ACE and ACE2 have been implicated in several pathologies such as cardiovascular and renal disease or acute lung injury. In addition, ACE2 has functions independent of the RAS: ACE2 is the receptor for the SARS coronavirus and ACE2 is essential for expression of neutral amino acid transporters in the gut. In this context, ACE2 modulates innate immunity and influences the composition of the gut microbiota, which can explain diarrhea and intestinal inflammation observed in Hartnup disorder, Pellagra, or under conditions of severe malnutrition. Here we review and discuss the diverse functions of ACE2 and its relevance to human pathologies.     

外源性Apelin-13对心力衰竭大鼠血浆血管紧张素Ⅱ和肾上腺髓质素的影响

目的：研究给予外源性Apelin-13治疗对血流动力学、血浆血管紧张素Ⅱ（Angiotensin-Ⅱ,AngⅡ）和肾上腺髓质素（Adrenomedulin,ADM）水平的影响。方法：将50只大鼠随机分为3组：心衰组（n=20）、治疗组（n=20）和正常对照组（n=10）,阿霉素（ADR）腹腔注射建立大鼠心衰模型,治疗组给药外源性Apelin-13治疗,检测大鼠血浆AngⅡ和ADM水平（ELISA法）以及血流动力学的水平。结果：心衰组和治疗组血浆AngⅡ和ADM水平比正常对照组增高,但治疗组血浆AngⅡ和ADM水平比心衰组明显降低,治疗组左心室内压最大升降速度（LV±dp/dtmax）、左室最大收缩压（LVESP）比心衰组增高,左室舒张末期压（LVEDP）比心衰组低（P均〈0.05）。结论：外源性apelin-13抑制体内的AngⅡ和ADM水平可能对ADR诱导的大鼠心衰有保护作用。     

蛋白激酶C在血管紧张素Ⅱ诱导的肾小球系膜细胞收缩中的作用

目的：研究蛋白激酶C（pkc）在血管紧张素Ⅱ诱导的肾小球系膜细胞（GMC）收缩中的作用。方法：人肾小球系膜细胞系用于全部实验。应用血管紧张素Ⅱ（AngⅡ）刺激蛋白激酶C抑制剂白屈菜红碱（CHE）处理或来处理的系膜细胞。利用激光扫描共聚焦显微镜测细胞内钙离子浓度。结果：①膜细胞经AngⅡ诱导后,细胞出现明显的大幅度起始钙离子浓度升高（vs．control,p〈0．05,n=16）⑦膜细胞经CHE预处理后减少AngⅡ诱导的GMC钙离子浓度（vsAngⅡ,p〈O．05,n=16）。结论：①血管紧张素Ⅱ诱导系膜细胞收缩。②蛋白激酶C参与血管紧张素Ⅱ诱导的肾小球系膜细胞的收缩过程。     

Increased urinary angiotensin-converting enzyme 2 in renal transplant patients with diabetes

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme, since it converts angiotensin (Ang) II to Ang-(1-7). ACE2 has been detected in urine from patients with chronic kidney disease. We measured urinary ACE2 activity and protein levels in renal transplant patients (age 54 yrs, 65% male, 38% diabetes, n?=?100) and healthy controls (age 45 yrs, 26% male, n?=?50), and determined factors associated with elevated urinary ACE2 in the patients. Urine from transplant subjects was also assayed for ACE mRNA and protein. No subjects were taking inhibitors of the renin-angiotensin system. Urinary ACE2 levels were significantly higher in transplant patients compared to controls (p?=?0.003 for ACE2 activity, and p≤0.001 for ACE2 protein by ELISA or western analysis). Transplant patients with diabetes mellitus had significantly increased urinary ACE2 activity and protein levels compared to non-diabetics (p<0.001), while ACE2 mRNA levels did not differ. Urinary ACE activity and protein were significantly increased in diabetic transplant subjects, while ACE mRNA levels did not differ from non-diabetic subjects. After adjusting for confounding variables, diabetes was significantly associated with urinary ACE2 activity (p?=?0.003) and protein levels (p<0.001), while female gender was associated with urinary mRNA levels for both ACE2 and ACE. These data indicate that urinary ACE2 is increased in renal transplant recipients with diabetes, possibly due to increased shedding from tubular cells. Urinary ACE2 could be a marker of renal renin-angiotensin system activation in these patients.     

Angiotensin-converting enzyme 2 autoantibodies: further evidence for a role of the renin-angiotensin system in inflammation

Traditionally viewed as important in the regulation of blood pressure, the renin-angiotensin system - and specifically the angiotensin-converting enzyme (ACE)-angiotensin (Ang) II-AT₁ receptor axis - may play a prominent role to promote inflammation and fibrosis. ACE2, a new component of the renin-angiotensin system, has emerged as a key enzyme that selectively degrades Ang II and generates Ang-(1-7), a bioactive peptide with anti-inflammatory and anti-fibrotic actions. Takahashi and colleagues demonstrate circulating titers of inhibitory autoantibodies against ACE2 in patients with systemic sclerosis. The current study reveals a potentially novel mechanism to attenuate the catalytic activity of ACE2, thereby promoting the actions of Ang II.