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。     

ACE2及其特殊功能

血管紧张素转换酶2（angiotensin—converting enzyme 2,ACE2）是新发现的与血管紧张素转换酶（ACE）相关的羧肽酶,在肾素-血管紧张素系统（rennin-angiotensin system,RAS）中ACE2可以使AngⅡ转换为Ang1-7,从而产生与血管紧张素Ⅱ相反的效应,同时ACE2还可使Ang I转换为Ang1-9。研究发现：ACE2与高血压、SARS以及肾脏、生殖等系统的疾病有着密切的关系。     

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。     

ACE2在SARS发病中作用的研究进展

重症急性呼吸综合征（SARS）是由SARS冠状病毒（SARS-CoV）引起的一种急性传染病,在其序列被测出后几个月内人们就找到了SARS-CoV的受体血管紧张素转换酶2（ACE2）。因病毒受体与病毒入侵细胞密切相关,因而有必要深入研究ACE2与SARS-CoV之间的关系。本文总结了ACE2在各组织器官的分布及功能,分析了ACE2基因的变异与病毒进入及SARS疾病严重程度之间的关系、ACE2基因的表达水平与病毒进入及SARS疾病严重程度之间的关系。这些研究将为理解SARS-CoV与ACE2之间的相互作用及设计针对ACE2的抗SARS药物提供重要的理论依据。     

乳酸菌发酵产品的降血压功能及其机制

1概述 血压是目前最为广泛的心血管疾病,据世界卫生组织（WHO）估计,全球患病人数已超过5亿.它是冠心病、脑卒死、心及肾功能衰竭的最主要发病因素,预防和治疗高血压将有助于降低心血管系统疾病的风险.高血压是由多方面因素引发的,如精神、神经、内分泌、遗传及血管紧张素转化酶（Angiotensin Ⅰ-converting enzyme,ACE）活性等,尤以ACE在血压调节过程中起关键作用.如图1所示,一方面,无活性的血管紧张素原在肾素的作用下转化为血管紧张素Ⅰ,血管紧张素Ⅰ在ACE的作用下转化为血管紧张素Ⅱ,血管紧张素Ⅱ能刺激血管收缩使血压升高,同时血管紧张素Ⅱ也能促使醛固酮分泌,直接对肾脏作用,引起纳储量和血容量增加也使血压升高.与此相反,缓激肽是降压物质,它能促使血管扩张和刺激扩血管物质前列腺素的合成增加,二者共同作用使血压下降.而在ACE的作用下,缓激肽分解成失活片断.如果人体内ACE活性过高,就会使血管紧张素Ⅱ生成增加,同时缓激肽被大大破坏,导致血压升高.     

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.     

血管紧张肽转化酶2与肾素-血管紧张肽系统的研究进展

肾素-血管紧张肽系统（RAS）在维持血压稳态、水盐平衡,及局部组织器官的正常功能等方面具有重要的作用。局部RAS的失衡将导致这些器官的疾病。血管紧张肽转化酶2（ACE2）是ACE的同源物,作为RAS的重要负调节因子,平衡血管紧张肽Ⅱ的产生,维持循环系统和局部组织中RAS的稳态。本文综述了在心血管、肺、肾、肝等器官的多种急、慢性疾病患者或动物模型中,RAS与ACE2所发挥的重要作用。     

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。     

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。     

血管紧张素—（1—7）——肾素血管紧张素系统的新激素

长期以来,血管紧张素－（１－７）「Ａｎｇ－（１－７））」－直被认为是血管紧张素Ⅱ的无生物活性代谢产物。近年的研究证明Ａｎｇ－（１－７）在神经系统和心血管功能调节中起有作用,是血管紧张素系统中一种新的重要激素。     

Meta-Analysis of Combined Therapy with Angiotensin Receptor Antagonists versus ACE Inhibitors Alone in Patients with Heart Failure

Background

There is insufficient evidence whether the benefit of adding angiotensin II receptor blockers (ARBs) to angiotensin-converting enzyme (ACE) inhibitors outweighs the increased risk of adverse effects in patients with heart failure.

Methodology/Principal Findings

Two independent reviewers searched and abstracted randomized controlled trials of ARBs and ACE inhibitors compared to ACE inhibitor therapy alone in patients with heart failure reporting mortality and hospitalizations having a follow-up of at least 6 months identified by a systematic literature search. Eight trials including a total of 18,061 patients fulfilled our inclusion criteria. There was no difference between patients treated with combination therapy and ACE inhibitor therapy alone for overall mortality, hospitalization for any reason, fatal or nonfatal MI. Combination therapy was, however, associated with fewer hospital admissions for heart failure (RR 0.81, 95%CI 0.72–0.91), although there was significant heterogeneity across trials (p-value for heterogeneity = 0.04; I² = 57% [95%CI 0–83%]). Patients treated with combination therapy had a higher risk of worsening renal function and symptomatic hypotension, and their trial medications were more often permanently discontinued. Lack of individual patient data precluded the analysis of time-to-event data and identification of subgroups which potentially benefit more from combination therapy such as younger patients with preserved renal function and thus at lower risk to experience worsening renal function or hyperkalemia.

Conclusions/Significance

Combination therapy with ARBs and ACE inhibitors reduces admissions for heart failure in patients with congestive heart failure when compared to ACE inhibitor therapy alone, but does not reduce overall mortality or all-cause hospitalization and is associated with more adverse events. Thus, based on current evidence, combination therapy with ARBs and ACE inhibitors may be reserved for patients who remain symptomatic on therapy with ACE inhibitors under strict monitoring for any signs of worsening renal function and/or symptomatic hypotension.     

ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function

Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2(-/y)) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2(-/y). Post infusion, plasma and brain AngII levels were also significantly higher in ACE2(-/y), although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2(-/y) mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2(-/y) mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2(-/y) mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress.     

ACE2/Ang-(1–7) signaling and vascular remodeling

The renin-angiotensin system (RAS) regulates vascular tone and plays a critical role in vascular remodeling, which is the result of a complex interplay of alterations in vascular tone and structure. Inhibition of the RAS has led to important pharmacological tools to prevent and treat vascular diseases such as hypertension, diabetic vasculopathy and atherosclerosis. Angiotensin converting enzyme 2 (ACE2) was recently identified as a multifunctional monocarboxypeptidase responsible for the conversion of angiotensin (Ang) II to Ang-(1–7). The ACE2/Ang-(1–7) signaling has been shown to prevent cellular proliferation, pathological hypertrophy, oxidative stress and vascular fibrosis. Thus, the ACE2/Ang-(1–7) signaling is deemed to be beneficial to the cardiovascular system as a negative regulator of the RAS. The addition of the ACE2/Ang-(1–7) signaling to the complexities of the RAS may lead to the development of novel therapeutics for the treatment of hypertension and other vascular diseases. The present review considers recent findings regarding the ACE2/Ang-(1–7) signaling and focuses on its regulatory roles in processes related to proliferation, inflammation, vascular fibrosis and remodeling, providing proof of principle for the potential use of ACE2 as a novel therapy for vascular disorders related to vascular remodeling.     

ACE2: A novel therapeutic target for cardiovascular diseases

Hypertension afflicts over 65 million Americans and poses an increased risk for cardiovascular morbidity such as stroke, myocardial infarction and end-stage renal disease resulting in significant mortality. Overactivity of the renin-angiotensin system (RAS) has been identified as an important determinant that is implicated in the etiology of these diseases and therefore represents a major target for therapy. In spite of the successes of drugs inhibiting various elements of the RAS, the incidence of hypertension and cardiovascular diseases remain steadily on the rise. This has lead many investigators to seek novel and innovative approaches, taking advantage of new pathways and technologies, for the control and possibly the cure of hypertension and related pathologies. The main objective of this review is to forward the concept that gene therapy and the genetic targeting of the RAS is the future avenue for the successful control and treatment of hypertension and cardiovascular diseases. We will present argument that genetic targeting of angiotensin-converting enzyme 2 (ACE2), a newly discovered member of the RAS, is ideally poised for this purpose. This will be accomplished by discussion of the following: (i) summary of our current understanding of the RAS with a focus on the systemic versus tissue counterparts as they relate to hypertension and other cardiovascular pathologies; (ii) the newly discovered ACE2 enzyme with its physiological and pathophysiological implications; (iii) summary of the current antihypertensive pharmacotherapy and its limitations; (iv) the discovery and design of ACE inhibitors; (v) the emerging concepts for ACE2 drug design; (vi) the current status of genetic targeting of the RAS; (vii) the potential of ACE2 as a therapeutic target for hypertension and cardiovascular disease treatment; and (viii) future perspectives for the treatment of cardiovascular diseases.     

The frequency of factor V Leiden mutation,ACE gene polymorphism,serum ACE activity and response to ACE inhibitor and angiotensin II receptor antagonist drugs in Iranians type II diabetic patients with microalbuminuria

The aim of present study was to determine if factor V Leiden (FVL) mutation and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism are associated with diabetic nephropathy (DN) among Kurdish population from Western Iran. This case–control study comprised 144 unrelated adult type 2 diabetic mellitus patients (T2DM) including 72 patients with microalbuminuria and 72 age and sex matched patients without nephropathy. The ACE I/D polymorphism and FVL mutation were detected by polymerase chain reaction (PCR) and PCR–RFLP, respectively. The frequency of FVL G1691A and ACE D allele in T2DM patients with microalbuminuria were 1.6 and 57%, respectively and in normoalbuminuric T2DM patients were 4.9 and 58.3%, respectively (P > 0.05). ACE genotypes affected on serum ACE activity and a better response to ACE inhibitor therapy (captopril) compared to angiotensin II receptor antagonist (losartan) was obtained with significant reduction of ACE activity in diabetic patients without nephropathy carrying DD genotype. However, the beneficial effect of losartan therapy was observed in microalbuminuric patients with II genotype compared to ID and DD genotypes.     

Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements, and chloride dependence

Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, represents a new and potentially important target in cardio-renal disease. A model of the active site of ACE2, based on the crystal structure of testicular ACE, has been developed and indicates that the catalytic mechanism of ACE2 resembles that of ACE. Structural differences exist between the active site of ACE (dipeptidyl carboxypeptidase) and ACE2 (carboxypeptidase) that are responsible for the differences in specificity. The main differences occur in the ligand-binding pockets, particularly at the S2' subsite and in the binding of the peptide carboxy-terminus. The model explains why the classical ACE inhibitor lisinopril is unable to bind to ACE2. On the basis of the ability of ACE2 to cleave a variety of biologically active peptides, a consensus sequence of Pro-X-Pro-hydrophobic/basic for the protease specificity of ACE2 has been defined that is supported by the ACE2 model. The dipeptide, Pro-Phe, completely inhibits ACE2 activity at 180 microM with angiotensin II as the substrate. As with ACE, the chloride dependence of ACE2 is substrate-specific such that the hydrolysis of angiotensin I and the synthetic peptide substrate, Mca-APK(Dnp), are activated in the presence of chloride ions, whereas the cleavage of angiotensin II is inhibited. The ACE2 model is also suggestive of a possible mechanism for chloride activation. The structural insights provided by these analyses for the differences in inhibition pattern and substrate specificity among ACE and its homologue ACE2 and for the chloride dependence of ACE/ACE2 activity are valuable in understanding the function and regulation of ACE2.     

Dual deficiency of angiotensin‐converting enzyme‐2 and Mas receptor enhances angiotensin II‐induced hypertension and hypertensive nephropathy

Angiotensin‐converting enzyme‐2 (ACE2) and Mas receptor are the major components of the ACE2/Ang 1‐7/Mas axis and have been shown to play a protective role in hypertension and hypertensive nephropathy individually. However, the effects of dual deficiency of ACE2 and Mas (ACE2/Mas) on Ang II‐induced hypertensive nephropathy remain unexplored, which was investigated in this study in a mouse model of hypertension induced in either ACE2 knockout (KO) or Mas KO mice and in double ACE2/Mas KO mice by subcutaneously chronic infusion of Ang II. Compared with wild‐type (WT) animals, mice lacking either ACE2 or Mas significantly increased blood pressure over 7‐28 days following a chronic Ang II infusion (P < .001), which was further exacerbated in double ACE2/Mas KO mice (P < .001). Furthermore, compared to a single ACE2 or Mas KO mice, mice lacking ACE2/Mas developed more severe renal injury including higher levels of serum creatinine and a further reduction in creatinine clearance, and progressive renal inflammation and fibrosis. Mechanistically, worsen hypertensive nephropathy in double ACE2/Mas KO mice was associated with markedly enhanced AT1‐ERK1/2‐Smad3 and NF‐κB signalling, thereby promoting renal fibrosis and renal inflammation in the hypertensive kidney. In conclusion, ACE2 and Mas play an additive protective role in Ang II‐induced hypertension and hypertensive nephropathy. Thus, restoring the ACE2/Ang1‐7/Mas axis may represent a novel therapy for hypertension and hypertensive nephropathy.     

Inhibition of SARS-CoV-2 pseudovirus invasion by ACE2 protecting and Spike neutralizing peptides: An alternative approach to COVID19 prevention and therapy

SARS-CoV-2 invades host cells mainly through the interaction of its spike-protein with host cell membrane ACE2. Various antibodies targeting S-protein have been developed to combat COVID-19 pandemic; however, the potential risk of antibody-dependent enhancement and novel spike mutants-induced neutralization loss or antibody resistance still remain. Alternative preventative agents or therapeutics are still urgently needed. In this study, we designed series of peptides with either ACE2 protecting or Spike-protein neutralizing activities. Molecular docking predicted that, among these peptides, ACE2 protecting peptide AYp28 and Spike-protein neutralizing peptide AYn1 showed strongest intermolecular interaction to ACE2 and Spike-protein, respectively, which were further confirmed by both cell- and non-cell-based in vitro assays. In addition, both peptides inhibited the invasion of pseudotype SARS-CoV-2 into HEK293T/hACE2 cells, either alone or in combination. Moreover, the intranasal administration of AYp28 could partially block pseudovirus invasion in hACE2 transgenic mice. Much more importantly, no significant toxicity was observed in peptides-treated cells. AYp28 showed no impacts on ACE2 function. Taken together, the data from our present study predicted promising preventative and therapeutic values of peptides against COVID-19, and may prove the concept that cocktail containing ACE2 protecting peptides and spike neutralizing peptides could serve as a safe and effective approach for SARS-CoV-2 prevention and therapy.     

Repurposing of approved drugs with potential to interact with SARS-CoV-2 receptor

Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 surface spike glycoprotein for entry into human cells. A recent study reported absent to low expression of ACE2 in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE1 (a homolog of ACE2 and also known as ACE) in human lungs compared to very low expression of ACE2. In fact, ACE1 has a wider and more abundant tissue distribution compared to ACE2. Although it is not obvious from the primary sequence alignment of ACE1 and ACE2, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Critical amino acids in ACE2 that mediate interaction with the viral spike protein are present and organized in the same order in the PD of ACE1. In silico analysis predicts comparable interaction of SARS-CoV-2 spike protein with ACE1 and ACE2. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 and/or ACE1 and potentially interfere with the entry of SARS-CoV-2 inside the host cells.