ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension,multi-organ failure,and COVID-19 disease outcome

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged in Chinese people in December 2019 and has currently spread worldwide causing the COVID-19 pandemic with more than 150,000 deaths. In order for a SARS-CoV like virus circulating in wild life for a very long time to infect the index case-patient, a number of conditions must be met, foremost among which is the encounter with humans and the presence in homo sapiens of a cellular receptor allowing the virus to bind. Recently it was shown that the SARS-CoV-2 spike protein, binds to the human angiotensin I converting enzyme 2 (ACE2). This molecule is a peptidase expressed at the surface of lung epithelial cells and other tissues, that regulates the renin-angiotensin-aldosterone system. Humans are not equal with respect to the expression levels of the cellular ACE2. Moreover, ACE2 polymorphisms were recently described in human populations. Here we review the most recent evidence that ACE2 expression and/or polymorphism could influence both the susceptibility of people to SARS-CoV-2 infection and the outcome of the COVID-19 disease. Further exploration of the relationship between the virus, the peptidase function of ACE2 and the levels of angiotensin II in SARS-CoV-2 infected patients should help to better understand the pathophysiology of the disease and the multi-organ failures observed in severe COVID-19 cases, particularly heart failure.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

血清血管紧张素转换酶的水平在阻塞性睡眠呼吸暂停低通气综合征患者中的变化研究

目的检测阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者中血清血管紧张素转换酶(ACE)水平的变化及其临床意义。方法设置OSAHS组(n=40)和健康对照组(n=40),测定并比较患者的血压、血脂和血清ACE水平在两组间的差异;分析ACE水平与患者病情变化、血压、血脂的相关性。结果 OSAHS患者在体重、BMI指数、颈围、腰围、AHI、收缩压、舒张压、TC、LDL-C和血清ACE方面高于健康人(P体重=0.002,P颈围=0.024,P腰围=0.038,PBMI=0.019,PAHI=0.001,P收缩压=0.001,P舒张压=0.001,PTC=0.017,PLDL-C=0.010,PACE=0.039),在LSa O2上低于健康人(PLSa O2=0.001)。OSAHS患者的收缩压、TC、ACE在轻中度和中重度之间均存在统计学差异(P收缩压=0.018、0.043,PTC=0.045、0.034,PACE=0.030、0.001),相关性分析显示,OSAHS患者中血清ACE与收缩压和TC均呈正相关(r=0.35,P=0.017;r=0.28,P=0.044)。结论 OSAHS患者血清ACE能反映患者病情的变化,并与血压和血脂具有一定相关性。     

Current treatment of hypertension in patients with coronary artery disease recommended by different guidelines

Introduction: It is important to know how to treat hypertension in patients with coronary artery disease (CAD). The reason for the review was to update this treatment and to discuss the 2015 American Heart Association/American College of Cardiology/American Society of Hypertension 2015 guidelines of treatment of hypertension in patients with CAD.

Areas covered: Studies between 1968 and 2015 were reviewed on treatment of hypertension in patients with CAD using a Medline search, and studies between 1977 and 2015 were reported. Hypertension should be treated with beta blockers and ACE inhibitors or angiotensin receptor blockers (ARBs). Long-acting nitrates are effective antianginal and anti-ischemic drugs. Calcium-channel blockers (CCBs) may be added if angina persists despite beta blockers and long-acting nitrates. The 2015 guidelines recommend that the blood pressure should be < 140/90 mm Hg in patients aged ≤ 80 years and the systolic blood pressure < 150 mm Hg if they are ≥ 80 years.

Expert opinion: Hypertension in patients with CAD should be treated with beta blockers and ACE inhibitors or ARBs. Long-acting nitrates are effective antianginal and anti-ischemic drugs. CCBs may be added if angina persists despite beta blockers and long-acting nitrates. The blood pressure should be < 140/90 mm Hg in patients aged < 80 years and the systolic blood pressure < 150 mm Hg if they are ≥ 80 years.     

中国优秀马拉松运动员ACE基因I/D多态性频率分布特征

通过分析中国马拉松运动员ACE基因I/D多态频率分布特征,探讨其作为杰出耐力基因标记的可行性。选择我国马拉松健将、国际健将级运动员26名作为马拉松运动员组,汉族学生216名作为对照组。对两组受试者进行ACE基因I/D多态性测定。结果显示:我国马拉松运动员组的等位基因频率和基因型频率与对照组比较无显著差异,其中15名国际健将中无一DD型纯合子,提示我国优秀马拉松运动员的纯合子DD型频率低下是其ACE基因多态频率分布的主要特征。     

Pharmacokinetics and pharmacodynamics of benazepril hydrochloride in patients with major proteinuria

Summary We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o.The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients.Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42 %. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients.In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.     

The Bradykinin-potentiating peptides from venom gland and brain of Bothrops jararaca contain highly site specific inhibitors of the somatic angiotensin-converting enzyme

Pyroglutamyl, proline-rich oligopeptides, classically referred to as bradykinin-potentiating peptides (BPPs) are found in Bothrops jararaca venom, and are naturally occurring inhibitors of the somatic angiotensin-converting enzyme (ACE). The chemical and pharmacological properties of these peptides were essential for the development of captopril, the first active site directed inhibitor of ACE, currently used to treat human hypertension. ACE is a complex ectoenzyme of the vascular endothelium, possessing two catalytic sites, performing diverse specific roles. Recent advances concerning novel features of BPPs revealed that they might still contribute to a better understanding of the cardiovascular physiology and pathology. The molecular biology of the BPPs revealed that they are part of two distinct C-type natriuretic peptide precursors found in the venom gland and the brain of B. jararaca, each containing seven BPPs. In situ hybridization studies detected the presence of the corresponding mRNA precursor in snake brain regions correlated with neuroendocrine functions, such as the ventro-medial hypothalamus, the paraventricular nuclei, the paraventricular organ, and the subcommissural organ. In this article we discuss the large variety of homologous BPPs in B. jararaca venom and brain, its significance, and whether the BPPs could represent novel endogenous neuropeptides.     

上海地区汉族优秀游泳运动员ACE基因I/D多态性研究

目的:探讨上海地区汉族不同水平优秀游泳运动员ACE(血管紧张素转化酶)基因I/D多态性的分布特点。方法:采用PCR方法,对上海地区85名汉族优秀游泳运动员和90名汉族普通人的ACE基因I/D多态性进行检测。结果显示,上海地区汉族优秀游泳运动员的ACE基因的基因型和等位基因频率与上海和成都地区汉族普通人无明显差异(P>0.05);上海地区汉族游泳运动员和普通人以及成都地区汉族普通人的基因型和等位基因频率均与高加索人群存在高度显著性差异(P<0.0001),表现出明显的种族差异性。7名上海地区汉族国际健将ACE基因均为II型,运动水平越高的组别,II基因型和I等位基因频率越高,提示具有II基因型或I等位基因频率高的运动员经过多年运动训练,具有成为优秀运动员的可能,特别是II基因型的运动员可能性更大。