ACE2-Ang-（1—7）-Mas轴：心血管疾病治疗的新靶点

肾素一血管紧张素系统(RAS)在哺乳动物心血管活动的调节中发挥了重要的作用.随着血管紧张素转化酶(ACE)2和血管紧张素1-7[Ang-(1-7)]特异性受体Mas的发现,形成了RAS中一个对心血管有益的新分支:ACE2-Ang-(1-7)-Mas轴.其中ACE2可以水解血管紧张素Ⅰ(Ang Ⅰ)、血管紧张素Ⅱ(AngⅡ)生成Ang-(1-7).Ang-(1-7)则通过Mas受体拮抗AngⅡ的作用,引起血管舒张、抑制细胞增殖.这一新分支的发现为心血管疾病的治疗提供了新靶点.     

血管紧张素-(1-7)的心血管调节作用

血管紧张素-(1-7)[Ang-(1—7)]是肾素-血管紧张素系统(RAS)的新成员,在许多方面拮抗血管紧张素Ⅱ(AngⅡ),具有扩张血管、降低血压、利钠、利尿、抗增生及抗炎症等作用。其作用由特异性受体介导,与缓缴肽、一氧化氮及.PGI2有关。新近发现的血管紧张素转换酶2(ACE2)与Ang-(1-7)构成RAS的一轴即ACE2-Ang-(1-7)轴,与另外一轴即ADE-AngⅡ轴是对立统一的关系,两轴间的平衡对维持心血管、泌尿、生殖等系统的正常功能起重要作用。     

ACE2-Ang-（1—7）-Mas轴：心血管疾病治疗的新靶点

肾素-血管紧张素系统（RAS）在哺乳动物心血管活动的调节中发挥了重要的作用。随着血管紧张素转化酶（ACE）2和血管紧张素1—7[Ang-（1-7）]特异性受体Mas的发现,形成了RAS中一个对心血管有益的新分支：ACE2-Ang-（1-7）-Mas轴。其中ACE2可以水解血管紧张素Ⅰ（AngⅠ）、血管紧张素Ⅱ（AngⅡ）生成Ang-（1-7）。Ang（1-7）则通过Mas受体拮抗AngⅡ的作用,引起血管舒张、抑制细胞增殖。这一新分支的发现为心血管疾病的治疗提供了新靶点。     

血管紧张素转换酶2与心血管疾病研究进展

正肾素-血管紧张素系统(RAS)是人体内重要的体液调节系统,在心血管疾病的病理生理过程中发挥直接作用。在RAS血管紧张素原在肾素的作用下裂解为血管紧张素(Ang)Ⅰ,而血管紧张素转换酶(ACE)使AngⅠ转换生成AngⅡ。AngⅡ是RAS中主要活性物质,一方面,通过血管收缩、水钠潴溜导致血压升高,另一方面引起心肌重构、炎症、血栓形成及斑块破裂等~([1])。应用血管紧张素转换酶抑制剂(ACEI)及AngⅡ受体阻滞剂(ARB)可达到降压、延缓心肌重构等治     

ACE2-Ang-(1-7)-MAS轴及其研究进展

肾素-血管紧张素系统(RAS)是一种经典的循环酶通路,研究证实,血管紧张素(Ang)Ⅱ是这一通路的重要代谢产物,在RAS中起重要生物学作用.血管紧张素转换酶2(ACE2)是新近发现的一种血管紧张素转换酶,该酶的主要转化产物为Ang1～Ang7[以下简写为 Ang-(l-7)]及其受体MAS,现就ACE2-Ang-(l-7)-MAS轴及其研究进展作一综述.     

ACE2-Ang(1-7)-Mas轴与心房颤动的关系

在肾素-血管紧张素系统(RAS)中,血管紧张素转化酶2(ACE2)与血管紧张素(AngⅡ)之间的代谢关系在ACE2-Ang(1-7)-Mas轴保护心房颤动(房颤)的心肌细胞作用中发挥着重要作用.作为ACE的唯一同系物,ACE2可以水解AngⅡ为七肽Ang(1-7),而Ang(1-7)可以特异性激活Mas受体,发挥抗纤维...     

肾素-血管紧张素系统的回顾

肾素-血管紧张素系统(RAS)新成员的发现,改变了既往认为只有血管紧张素转化酶(ACE)催化生成的血管紧张素(Ang)Ⅱ才产生致病作用的观点,证明肾素与前肾素-肾素受体(RPR)的结合及AngⅣ与胰岛素调控氨基肽酶受体(IRAP)的结合同样也会产生致病作用。新发现的ACE2催化Ang-(1-7)和Ang-(1-9)的生成,Ang-(1-7)与Mas受体和Ang-(1-9)与AT2受体结合之后,可产生心血管保护作用,但RAS的致病作用仍然占优势。RAS新成员的发现,对认识RAS抑制剂的临床研究结果提供了新的理论依据。     

血管紧张素转换酶2研究新进展

血管紧张素转换酶(ACE)是一种锌指金属蛋白酶,对肾素-血管紧张素系统(RAS)有关键调控作用.ACE 2主要分布在心脏、肾脏和睾丸,能水解血管紧张素(Ang)Ⅰ,产生Ang 1-9,还能水解RAS中的主要物质AngⅡ,产生具有血管扩张作用的Ang 1-7.研究表明ACE 2可能在RAS中扮演与ACE相反的角色,达到血管收缩和舒张之间的平衡,与高血压、心力衰竭及糖尿病肾病等关系密切.     

血管紧张素转换酶2-Ang(1-7)-Mas轴心血管效应的研究进展

肾素-血管紧张素系统(RAS)是一个重要的血压和水电解质调节系统,在心血管疾病的发生、发展中具有非常重要的作用。新近发现,循环和局部的RAS还包括血管紧张素转换酶(ACE)同族物——ACE2及各种旁代谢产物:如血管紧张素(Ang1-7、Ang3-8、Ang2-7)以及肾素受体和Ang1-7受体Mas等。ACE2与Ang1-7、Mas受体共同构成的ACE2-Ang(1-7)-Mas轴,成为RAS的另一重要分支,能对抗AngⅡ的作用。由于RAS的复杂性,促使了进一步研究该系统在心血管疾病中的作用机制。本文就该轴在心血管疾病中作用的研究进展作一综述。     

肝纤维化形成中血管紧张素(1-7)及其转换酶与胰岛素样生长因子结合蛋白2的动态变化

肝脏存在局部肾素-血管紧张素系统(RAS),血管紧张素Ⅱ(AngⅡ)是其主要介质,AngⅡ在肝星状细胞活化与纤维增生中起重要作用.近年发现血管紧张素转换酶2(ACE2)及其代谢产物Ang-(1-7),Ang-(1-7)可通过Mas受体拮抗AngⅡ的作用,引起血管舒张、抑制细胞增殖[1].胰岛素样生长因子结合蛋白2(IGFBP-2)主要由肝实质细胞产生和表达,与肝纤维化的形成关系密切[2].但对Ang-(1-7)、ACE2及IGFBP-2在肝纤维化形成过程中的动态变化报道较少.因此,本实验采用CC14诱导的大鼠肝纤维化模型作为研究对象,探讨ACE2、Ang-(1-7)、IGFBP-2在大鼠肝纤维化形成过程中的动态变化.     

Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

AIM： To evaluate the effect of β-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. METHODS： Patients were allocated into two groups： outpatients with advanced liver disease（LD） and during liver transplantation（LT）. Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity（PRA）, Angiotensin（Ang） Ⅰ, Ang Ⅱ, and Ang-（1-7） levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system（RAS） components.RESULTS： PRA, Ang Ⅰ, Ang Ⅱ and Ang-（1-7） were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-（1-7） and Ang Ⅰ levels and between Ang Ⅱand Ang Ⅰ were significantly increased in LD group receiving propranolol. The ratio between Ang-（1-7） and Ang Ⅱ remained unchanged in splanchnic and peripheral circulation in patients under β-blockade, whereas the relationship between Ang Ⅱ and Ang Ⅰ was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. CONCLUSION： In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-（1-7） and Ang Ⅱ in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.     

Relationship between angiotensin-（1-7） and angiotensin Ⅱ correlates with hemodynamic changes in human liver cirrhosis

AIM： To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system （RAS） components and hemodynamic changes. METHODS： Patients were allocated into 4 groups： mild-to-moderate liver disease （MLD）, advanced liver disease （ALD）, patients undergoing liver transplantation, and healthy controls. Blood was collected to determine plasma renin activity （PRA）, angiotensin （Ang） Ⅰ, Ang Ⅱ, and Ang-（1-7） levels using radioimmunoassays. During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components. RESULTS： PRA and angiotensins were elevated in ALD when compared to MLD and controls （P 〈 0.05）. In contrast, Ang Ⅱ was significantly reduced in MLD. Ang-（1-7）/Ang Ⅱ ratios were increased in MLD when compared to controls and ALD. During transplantation, Ang Ⅱ levels were lower and Ang-（1-7）/Ang Ⅱ ratios were higher in the splanchnic circulation than in the peripheral circulation （0.52 ± 0.08 vs 0.38 ±0.04, P 〈 0.02）, whereas the peripheral circulating Ang Ⅱ/Ang Ⅰ ratio was elevated in comparison to splanchnic levels （0.18 ±0.02 vs 0.13 ±0.02, P 〈 0.04）. Ang-（1-7）/ Ang Ⅱ ratios positively correlated with cardiac output （r = 0.66） and negatively correlated with systemic vascular resistance （r = -0.70）. CONCLUSION： Our findings suggest that the relationship between Ang-（1-7） and Ang Ⅱ may play a role in the hemodynamic changes of human cirrhosis.     

Angiotensin-(1-7): new perspectives in atherosclerosis treatment

Angiotensin (Ang)-(1-7) is recognized as a new bioactive peptide in renin-angiotensin system (RAS). Ang-(1-7) is a counter-regulatory mediator of Ang-II which appears to be protective against cardiovascular disease. Recent studies have found that Ang-(1-7) played an important role in reducing smooth muscle cell proliferation and migration, improving endothelial function and regulating lipid metabolism, leading to inhibition of atherosclerotic lesions and increase of plaque stability. Although clinical application of Ang-(1-7) is restricted due to its pharmacokinetic properties, identification of stabilized compounds, including more stable analogues and specific delivery compounds, has enabled clinical application of Ang-(1-7). In this review, we discussed recent findings concerning the biological role of Ang-(1-7) and related mechanism during atherosclerosis development. In addition, we highlighted the perspective to develop therapeutic strategies using Ang-(1-7) to treat atherosclerosis.     

血管紧张素Ⅱ、血管紧张素(1-7)对NIT-1细胞胰岛素信号通路的影响

目的 研究血管紧张素Ⅱ、血管紧张素(1-7)对胰岛β细胞胰岛素信号通路的影响.方法 小鼠胰岛β细胞株NIT-1予(1)0、10-7、10-6、10-5和10-4 mol/L浓度血管紧张素Ⅱ处理24h;(2)0、10-7、10-6、10-5和10-4mol/L浓度血管紧张素(1-7)处理24h;(3)血管紧张素Ⅱ、血管紧张素(1-7)联合处理24h,分为对照、10-5 mol/L血管紧张素Ⅱ、10-6 mol/L血管紧张素(1-7)、10-5 mol/L血管紧张素Ⅱ+10-6 mol/L血管紧张素(1-7)组.Western印迹检测胰岛素受体β亚基酪氨酸磷酸化(IR-β-Tyr)及蛋白激酶β丝氨酸磷酸化(Akt-Ser)水平.结果 血管紧张素Ⅱ浓度10-5和10-4mol/L时,胰岛素刺激的IR-β-Tyr、Akt-Ser表达显著降低;不同浓度血管紧张素(1-7)作用下,胰岛素刺激的IR-β-Tyr、Akt-Ser表达与对照组相比无差异;加入血管紧张素(1-7)共同孵育可逆转血管紧张素Ⅱ对Akt-Ser表达的抑制,而血管紧张素Ⅱ对IR-β-Tyr表达的抑制无效应.结论 在β细胞中,血管紧张素Ⅱ抑制胰岛素信号传导,血管紧张素(1-7)可拮抗血管紧张素Ⅱ对胰岛素刺激的Akt-Ser的抑制.     

Ang-(1-7)及AngⅡ对犬心房肌细胞外向钾通道电流的作用

目的观察Ang-(1-7)及AngⅡ对犬心房肌细胞外向钾通道电流的作用,揭示其参与房性心律失常的细胞电生理机制。方法急性分离单个犬心房肌细胞,采用全细胞膜片钳方法记录细胞膜快速延迟整流钾电流(Ikr)、缓慢延迟整流钾电流(Iks)、超快速延迟整流钾电流(Ikur)及短暂外向钾电流(Ito)。结果1μmol/LAng-(1-7)可抑制Ikr、Iks,增加Ito,对Ikur无明显影响;0.5μmol/LAngⅡ可增加Ikr、Iks,抑制Ito,对Ikur无明显影响。结论AngⅡ可能通过对外向钾电流的影响促进心房颤动的心房电重构,Ang-(1-7)作为AngⅡ内源性拮抗剂,可拮抗AngⅡ的电生理作用。     

血管紧张素(1-7)对血管紧张素Ⅱ诱导脐静脉内皮细胞表达E-选择素和单核细胞趋化蛋白1的影响

目的 研究血管紧张素(1-7)对血管紧张素Ⅱ诱导的脐静脉内皮细胞E-选择素和单核细胞趋化蛋白1表达的影响,并初步探讨血管紧张素(1-7)的作用机制,阐明血管紧张素(1-7)对血管紧张素Ⅱ在炎症方面的拮抗作用.方法 经形态学及抗VⅢ因子抗体免疫荧光染色鉴定的人脐静脉内皮细胞,按以下分组加入不同干扰因素进行实验.实验分组:①对照组:不加干预因素;②血管紧张素Ⅱ组:加入血管紧张素Ⅱ100 nmol/L;③血管紧张素(1-7)组:加入血管紧张素(1-7)1 000 nmol/L;④血管紧张素Ⅱ+血管紧张素(1-7)组:分别用血管紧张素(1-7)10、100、1 000、10 000 nmol/L预处理30 min后,再加入血管紧张素Ⅱ100 nmol/L;⑤血管紧张素Ⅱ+血管紧张素(1-7)+血管紧张素(1-7)受体拮抗剂A-779组:先用1 000 nmol/L A-779预处理30 min后,再用终浓度为1 000 nmol/L血管紧张素(1-7)预处理30 min,最后加入终浓度100 nmol/L血管紧张素Ⅱ.各组用酶联免疫吸附法和逆转录聚合酶链反应从蛋白和mRNA水平检测E-选择素和单核细胞趋化蛋白1的表达情况.结果 正常细胞生长良好,呈鹅卵石样镶嵌排列,细胞透明度大,轮廓不清.荧光免疫组化染色法,可检测到培养的人脐静脉内皮细胞的VⅢ因子相关抗原为阳性.①与对照组比,血管紧张素Ⅱ(100 nmol/L)使E-选择素(25.39±1.97μg/L)和单核细胞趋化蛋白1(238.71±5.51 ng/L)的蛋白分泌量明显增加, E-选择素和单核细胞趋化蛋白1 mRNA的表达显著升高(均P<0.01);②血管紧张素(1-7)(1 000 nmol/L)使E-选择素(3.72±0.95μg/L)和单核细胞趋化蛋白1(90.24±9.82 ng/L)的蛋白分泌量降低,E-选择素和单核细胞趋化蛋白1 mRNA表达亦降低(均P<0.01);③混合刺激组中血管紧张素(1-7)(10～10 000 nmol/L)减少E-选择素蛋白合成,分别为21.15±1.31、17.41±1.94、12.71±1.84、9.46±1.40μg/L,均低于血管紧张素Ⅱ组(均P<0.01);同时也减少单核细胞趋化蛋白1蛋白合成,分别为214.57±7.16、196.83±8.20、176.63±8.93、155.52±8.19 ng/L,均低于血管紧张素Ⅱ组(均P<0.01);④混合刺激组中,与AngⅡ组比较,血管紧张素(1-7)(10～10 000 nmol/L)呈剂量依赖性的抑制AngⅡ刺激E-选择素、单核细胞趋化蛋白1 mRNA的表达(均P<0.01);⑤加入血管紧张素(1-7)受体拮抗剂A-779后,血管紧张素(1-7)的作用消失.结论 血管紧张素(1-7)通过其特异性受体Mas拮抗血管紧张素Ⅱ诱导的人脐静脉内皮细胞E-选择素和单核细胞趋化蛋白1的表达,并呈浓度依赖性.     

血管紧张素-(1-7)对二肾一夹高血压大鼠血压及血管活性物质的影响

目的观察急性血管紧张素-(1-7)[Ang-(1-7)]干预后二肾一夹(2KlC)高血压大鼠血压的变化过程,以及Ang-(1-7)对血压相关血管活性物质的影响。方法建立2KlC高血压大鼠模型后2周,经颈内静脉予Ang-(1-7)短期干预,同时多导电生理仪记录有创颈动脉压演变。放免法测定血浆AngⅡ,酶法测定血清一氧化氮(NO)、氧自由基(O2-)浓度及血清总一氧化氮合酶(NOS)、超氧化物歧化酶(SOD)活力,酶免疫法测定血浆前列腺素E2(PGE2)。结果Ang-(1-7)可造成2KlC大鼠血压降低。与降低血压状态相伴随,血清NO及血浆PGE2浓度显著升高(P<0.01),血清O2-浓度显著降低(P<0.01),血浆AngⅡ水平及血清NOS、SOD活力未受Ang-(1-7)影响。结论在高肾素-血管紧张素系统(RAS)活性状态下,Ang-(1-7)降压机制与循环NO、PGE2浓度升高及O2-浓度降低有关。     

Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system （RAS） have progressively assumed an important role. Angiotensin （Ang） II acts as a profibrotic mediator and Ang-（1-7）, the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-（1-7）- Mas receptor axis.     

ACE2/Ang1-7/Mas在ALI/ARDS中作用机制研究

肾素-血管紧张素系统在 ALI/ARDS的病理过程中有重要作用。大约60% ARDS患者进展成肺纤维化且其病死率明显增加。目前研究显示 ACE/AngⅡ/AT1 R 与 ALI/ARDS 发病机制有关,而ACE2/Ang1-7/Mas起负向调节作用———ACE2和Ang1-7对ALI/ARDS有保护作用。因此,本文就 ACE2/Ang1-7/Mas在 ALI/ARDS中的保护作用和相关信号传导通路等方面最新研究进展作一阐述。     

Liver disease and the renin-angiotensin system: recent discoveries and clinical implications

The renin–angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type-1 receptor (AT₁) and, together with ACE, these components represent the 'classical' axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang-(1–7). Conceptually, ACE2, Ang-(1–7), and its putative receptor, the mas receptor represent an 'alternative' axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang-(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang-(1–7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.