血管紧张素转换酶2在新型冠状病毒感染及治疗中的作用概述

摘要：血管紧张素转换酶2(ACE2)是肾素-血管紧张素系统(RAS)重要的组成部分,能够下调RAS,具有抗炎、抗纤维化等作用。同时ACE2还是新型冠状病毒(SARS-CoV-2)的受体,与SARS-CoV-2感染及感染后的临床表现密切相关。血管紧张素转化酶抑制药/血管紧张素Ⅱ受体阻断药(ACEI/ARB)在SARS-CoV-2感染中的作用,目前研究尚有争议。本文对ACE2及ACEI/ARB类药物在SARS-CoV-2感染中的作用作一综述。基于目前的研究证据,建议感染前已使用ACEI/ARB类药物的新型冠状病毒肺炎(COVID-19)患者继续用药,但目前尚不建议将ACEI/ARB类药物用于COVID-19患者的治疗。     

拮抗血管紧张素与冠状动脉疾病

肾素-血管紧张素系统(RAS)是维持内环境稳定的一个复杂的级联系统,该系统过量表达会导致心血管疾病发生。抑制血管紧张素转化酶(ACE)和血管紧张素Ⅱ的Ⅰ型受体(AT1R)可降低心血管事件发生率和病死率。基于RAS抑制剂对心血管疾病的治疗作用,考虑RAS抑制剂有可能降低心肌血管重建术后缺血性事件的发生。然而,有关心肌血管重建术后冠脉血管再狭窄或再闭塞方面的研究数据并不一致。在多数研究中,血管紧张素转化酶抑制剂(ACEI)并不能降低心肌血管重建术后再狭窄的发生,相反,ACEI甚至与经皮冠脉介入(PCI)治疗后的再狭窄率升高有关;但选择性AT1R拮抗剂能降低PCI后的支架再狭窄。     

新型冠状病毒肺炎与血管紧张素转化酶2的研究现状

自2019年底起，新型冠状病毒肺炎（Coronavirus disease 2019，COVID-19）病例席卷全球。该病毒为β属冠状病毒，基因特征与严重急性呼吸综合征冠状病毒（Severe Acute Respiratory Syndrome Coronavirus，SARS-CoV）有较高相似性，被命名为2019新型冠状病毒（2019 Novel Coronavirus，2019-nCoV）或严重急性呼吸综合征冠状病毒-2（SARS-CoV-2），主要通过棘突蛋白介导与宿主血管紧张素转化酶2（angiotensin-converting enzyme 2，ACE2）受体结合侵犯人体。ACE2与COVID-19感染密切相关，既是SARS-CoV-2感染人体的关键靶点，ACE2表达多寡也是影响COVID-19患者疾病严重程度和死亡率的重要因素。因此靶向ACE2和肾素-血管紧张素系统（renin-angiotensin system，RAS）的诸多上市药物和在研药物，如血管紧张素转化酶抑制剂（angiotensin-converting enzyme inhibitor，ACEI）、血管紧张素受体拮抗剂（angiotensin receptor blocker，ARB）、重组人ACE2、Ⅱ型跨膜丝氨酸蛋白酶（type II transmembrane serine proteases，TMSPSS2）抑制剂、特异性中和抗体等都有可能成为治疗COVID-19的可行策略。此外，依据现有证据并不建议合并高血压的轻症COVID-19确诊病例或疑似病例轻易停用ACEI/ARB，以免造成血压波动。     

脑组织RAS与原发性高血压的关系

肾素-血管紧张素系统(renin-angiotensin system RAS)由肾素(Renin)、血管紧张素原(AGT)、血管紧张素转化酶(ACE)、血管紧张素(Ang)及其相应的受体构成.在多种因素的作用下,肾素释放增加,作用于血管紧张素原,使其生成10肽化合物血管紧张素I(Ang I);Ang I在ACE的作用下转化为血管紧张素Ⅱ(AngⅡ).     

ACE2研究新进展

血管紧张素转换酶2(ACE2)是近年来发现的肾素-血管紧张素系统(RAS)新成员,研究发现,ACE2与ACE作用相反,被认为对心血管系统有保护作用,在高血压、心力衰竭、冠心病、糖尿病肾病的发生、发展中具有重要作用。     

血管紧张素转换酶2在新型冠状病毒肺炎（COVID-19）发病机制及治疗中的作用研究进展

新型冠状病毒(SARS-CoV-2)感染导致严重的急性呼吸系统病变,其临床表现和肺部病理特征与急性肺损伤和急性呼吸窘迫综合征相似。已有研究表明,血管紧张素转换酶2(ACE2)为SARS冠状病毒(SARS-CoV)的功能受体。最近发现,SARS-CoV-2也可通过与细胞表面ACE2结合感染细胞,导致细胞病变和组织免疫损伤。人ACE2虽然是人ACE的同源物,但作为一种新型的金属羧肽酶,很多特性与ACE不同。ACE2在肾素-血管紧张素系统中具有独特的作用,参与维持肺的正常功能。ACE2是新型冠状病毒肺炎(COVID-19)病理途径中的关键因子,在COVID-19的临床治疗和药物研制中具有重要意义。     

肾素-血管紧张素系统的新成员:ACE2

血管紧张素转换酶2(angiotensin-converting enzyme 2,ACE2)是新发现的血管紧张素转换酶(ACE)的第一个同系物,ACE2与ACE结构虽部分相似,但功能特性却不同.在肾素-血管紧张素系统(rennin-angiotensin system,RAS)中ACE2与ACE共同参与血管紧张素代谢,调节心血管系统活动,研究发现ACE2与高血压、糖尿病以及肾脏、生殖等系统的疾病发生发展密切相关.本文就ACE2的新近研究进展做一综述.     

不同类型Goldblatt高血压大鼠对MK-421的降压反应

肾素—血管紧张素系统(RAS)与高血压发病机理密切相关。然而在不同高血压模型以及同一模型不同时期RAS在其发病中所起的作用大小不一。我们曾经报道血管紧张素Ⅰ转换酶(ACE)抑制剂巯甲丙脯酸灌胃能明显降低二肾一夹(2 K1C)型高血压大鼠的血压,但不降低一肾一夹(IK1C)型高血压大鼠的血压,MK-421是一种新的ACE抑制剂,化学名:N     

血管紧张素受体阻滞剂对自发性高血压大鼠肾脏血管紧张素转换酶2表达的影响

目的:研究自发性高血压大鼠肾脏血管紧张素转换酶2(ACE2)蛋白表达水平及血管紧张素ⅡⅠ型受体阻滞剂厄贝沙坦对ACE2表达的影响,以了解高血压的病理改变,探讨血管紧张素受体阻滞剂治疗高血压又一可能机制。方法:20只14周龄雄性自发性高血压大鼠随机分为自发性高血压大鼠(SHR)组(n=10)和厄贝沙坦组(n=10)。厄贝沙坦组每只大鼠以厄贝沙坦50mg·kg-1·d-1灌胃,给药时间12周。同时取14周龄雄性京都种Wistar大鼠为正常对照(WKY)组(n=10)。利用免疫组化和逆转录聚合酶链反应检测各组大鼠肾脏ACE2表达。结果:与WKY组比较,SHR组ACE2表达显著减少(0.72±0.11vs1.11±0.15);与SHR组比较,厄贝沙坦组经12周治疗后,ACE2表达明显提高(1.03±0.13vs0.72±0.11)。结论:高血压大鼠肾脏ACE2表达减少,血管紧张素ⅡⅠ型受体阻滞剂对高血压大鼠肾脏ACE2的表达有上调作用。此作用可能是血管紧张素受体阻滞除阻滞血管紧张素受体以外的另一间接调节肾素-血管紧张素系统的途径。     

血管紧张素转化酶2的研究进展

肾素一血管紧张素系统（renin—angiotensin system,RAS）是一复杂的调节系统,在维持机体血压稳定和水电解质平衡中发挥了主导作用,RAS活性的增强与心血管病以及由这些疾病所致的脏器损害（如：心脏、血管、肾脏等）存在相关性。血管紧张素转化酶（ACE）是肾素一血管紧张素系统的重要调节酶,而血管紧张素转化酶2（angiotensinconverting enzyme2,ACE2）是近年新发现的与ACE具有较高同源性的酶,     

The fight against COVID-19: Striking a balance in the renin–angiotensin system

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin–angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus Disease 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.     

Angiotensin-converting enzyme 2 in lung diseases

The renin-angiotensin system (RAS) plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance. Angiotensin II, a key effector peptide of the system, causes vasoconstriction and exerts multiple biological functions. Angiotensin-converting enzyme (ACE) plays a central role in generating angiotensin II from angiotensin I, and capillary blood vessels in the lung are one of the major sites of ACE expression and angiotensin II production in the human body. The RAS has been implicated in the pathogenesis of pulmonary hypertension and pulmonary fibrosis, both commonly seen in chronic lung diseases such as chronic obstructive lung disease. Recent studies indicate that the RAS also plays a critical role in acute lung diseases, especially acute respiratory distress syndrome (ARDS). ACE2, a close homologue of ACE, functions as a negative regulator of the angiotensin system and was identified as a key receptor for SARS (severe acute respiratory syndrome) coronavirus infections. In the lung, ACE2 protects against acute lung injury in several animal models of ARDS. Thus, the RAS appears to play a critical role in the pathogenesis of acute lung injury. Indeed, increasing ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases.     

Two important controversial risk factors in SARS-CoV-2 infection: Obesity and smoking

The effects of obesity and smoking in the coronavirus disease 2019 (COVID-19) pandemic remain controversial. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system (RAS), is the human cell receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. ACE2 expression increases on lung alveolar epithelial cells and adipose tissue due to obesity, smoking and air pollution. A significant relationship exists between air pollution and SARS-CoV-2 infection, as more severe COVID-19 symptoms occur in smokers; comorbid conditions due to obesity or excess ectopic fat accumulation as underlying risk factors for severe COVID-19 strongly encourage the virus/ACE2 receptor-ligand interaction concept. Indeed, obesity, air pollution and smoking associated risk factors share underlying pathophysiologies that are related to the Renin-Angiotensin-System in SARS-CoV-2 infection. The aim of this review is to emphasize the mechanism of receptor-ligand interaction and its impact on the enhanced risk of death due to SARS-CoV-2 infection.     

血管紧张素转换酶抑制剂/血管紧张素受体拮抗剂在新型冠状病毒肺炎疫情防控中的应用分析

根据《中国心血管病报告》,中国现患心血管病人数约2.9亿,而大量循证医学证据证实了血管紧张素转换酶抑制剂(ACEI)或血管紧张素受体拮抗剂(ARB)治疗心血管等疾病的价值.ACEI/ARB是肾素-血管紧张素-醛固酮系统(RAAS)的阻滞剂,可上调血管紧张素转换酶2(ACE2)表达水平.而ACE2是新型冠状病毒肺炎(CO...     

Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19

In late 2019, a new coronavirus emerged in Wuhan Province, China, causing lung complications similar to those produced by the SARS coronavirus in the 2002–2003 epidemic. This new disease was named COVID-19 and the causative virus SARS-CoV-2. The SARS-CoV-2 virus enters the airway and binds, by means of the S protein on its surface to the membrane protein ACE2 in type 2 alveolar cells. The S protein-ACE2 complex is internalized by endocytosis leading to a partial decrease or total loss of the enzymatic function ACE2 in the alveolar cells and in turn increasing the tissue concentration of pro-inflammatory angiotensin II by decreasing its degradation and reducing the concentration of its physiological antagonist angiotensin 1–7. High levels of angiotensin II on the lung interstitium can promote apoptosis initiating an inflammatory process with release of proinflammatory cytokines, establishing a self-powered cascade, leading eventually to ARDS. Recently, Gurwitz proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. In this commentary article, the authors make the case for the election of telmisartan as such alternative on the basis of its pharmacokinetic and pharmacodynamic properties and present an open-label randomized phase II clinical trial for the evaluation of telmisartan in COVID-19 patients ( NCT04355936 ).     

新型冠状病毒肺炎潜在的发病机制及间充质干细胞治疗作用的研究进展

摘要：新型冠状病毒肺炎（COVID-19）传染性强,重型患者病死率高,其发病机制尚不明确,缺乏特异性治疗方法。细胞因子风暴、免疫应答失衡可能是新型冠状病毒感染导致急性呼吸窘迫综合征（ARDS）及多脏器功能衰竭（MOF）甚至死亡的病生理基础。间充质干细胞（MSC）凭借其免疫调节、组织修复及抗纤维化等特性在COVID-19重症患者的救治中初显疗效,具有良好的临床应用前景。本文就COVID-19潜在的致病机制、MSC对COVID-19治疗的可能机制及在治疗中的应用进行综述,以期为临床治疗提供参考。     

Hypothesis: The potential therapeutic role of nicorandil in COVID-19

At present, there is yet no specific antiviral treatment or immunization against the newly identified human severe acute respiratory syndrome virus (SARS-CoV2) that results in a rapidly progressive pandemic coronavirus disease 2019 (COVID-19). We believe in a crucial need for a clinical strategy to counteract this viral pandemic based on the known pathogenesis throughout the disease course. Evidence suggests that exaggerated patient's inflammatory response and oxidative stress are likely to aggravate the disease pathology. The resulting endothelial dysfunction further induces fibrosis and coagulopathy. These disturbances can generate severe acute respiratory distress syndrome (ARDS) that can progress into respiratory and circulatory failure. Nicorandil is an anti-anginal vasodilator drug acts by increasing nitric oxide bioavailability and opening of the K_ATP channel. Recently, nicorandil has been recognized to possess multiple protective effects against tissue injury. Here, we address a possible modulatory role of nicorandil against COVID-19 pathogenesis. We hypothesise nicorandil would be an effective form of adjuvant therapy against COVID-19.     

Activation of protective and damaging components of the cardiac renin-angiotensin system after myocardial infarction in experimental diabetes.

INTRODUCTION: Diabetes is associated with prolonged apoptotic cell death of cardiac myocytes and adverse remodelling after myocardial infarction (MI). Because the renin-angiotensin system (RAS) has a major role in the remodelling, we studied whether diabetes is associated with altered regulation of RAS after MI in rats. METHODS: Male Wistar rats were randomised to receive either streptozotocin (diabetic group) or citrate buffer (control group) intravenously. MI was produced four weeks later by ligating the left descending coronary artery. The rats were sacrificed 1, 4 and 12 weeks after the operation. Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE 2), angiotensin type 1 and 2 receptors (AT(1)-receptor, AT(2)-receptor), and connective tissue growth factor (CTGF) mRNA expression were determined. RESULTS: The expression of both protective and damaging components of RAS increased after MI. However, myocardial ACE 2 and AT(2)-receptor messenger ribonucleic acid (mRNA) expression levels were significantly lower in diabetic compared to non-diabetic rats 1 week after MI. In contrast, AT(1)-receptor, ACE and CTGF mRNA levels were up-regulated in diabetic as compared with non-diabetic rats 12 weeks after MI. CONCLUSION: The activation of the protective components of RAS (ACE 2 and AT(2)-receptor) was blunted early after MI in diabetic rats, whereas the levels of ACE, AT(1)-receptor and CTGF mRNA leading to adverse effects on myocardium, were elevated in diabetic as compared with non-diabetic rats. This unbalanced activation of the RAS may influence the pathophysiology of myocardial injury in diabetes after MI.     

新型冠状病毒肺炎临床治疗药物最新研究进展

新型冠状病毒肺炎(coronavirus disease 2019,COVID-19)正在世界范围内流行.作为冠状病毒,新型冠状病毒(SARS-CoV-2)和严重急性呼吸综合征冠状病毒(SARS-CoV)都通过人血管紧张素转化酶2(ACE2)受体侵入宿主细胞.面对疫情异常严峻的现状,目前尚缺乏疫苗和尚无特异性针对该病毒...