Angiotensin-converting Enzyme 2 Level Research Articles

Serum levels of angiotensin converting enzyme 2 in patients with systemic sclerosis

BackgroundSystemic sclerosis (SSc) is an autoimmune disorder with fibrosis of the skin and internal organs. Angiotensin-converting enzyme 2 (ACE2) breaks down angiotensin II to the antifibrotic and anti-inflammatory angiotensin (1–7). Aim of the workTo assess the serum levels of ACE2 in SSc patients and to determine the association between its levels with the clinical features and disease severity. Patients and methodsSerum from 44 patients with SSc and 35 age and sex matched controls were assayed for ACE2 concentrations by enzyme linked immunosorbent assay. The modified Rodnan skin score (mRSS) was evaluated. ResultsPatients were 41 females and 3 males (F:M 13.7:1) with a mean age of 40.4 ± 11.3 years, and median disease duration of 5 years. Thirty-four patients had limited cutaneous SSc (lcSSc) and 10 had diffuse cutaneous SSc (dcSSc). Interstitial lung disease was present in 30 (68.2 %) patients. The median mRss was 11 (4–35). The antiscleroderma-70 and anticentromere antibodies were positive in 36.4 % and 29 %, respectively. The ACE2 level was significantly lower in SSc (1.02 ng/ml; 0.13–4.25 ng/ml) compared to control (1.57 ng/ml; 0.24–23.69 ng/ml) (p = 0.026) and in females compared to males (0.8; 0.13–4.15 ng/ml vs 3.33; 1.32–4.25 ng/ml) (p = 0.04) while the levels were comparable between lcSSc and dcSSc (p = 0.88). The level was lower in those with telangiectasia (n = 24), (p = 0.048) and in those receiving cyclophosphamide (n = 11), (p = 0.038) compared to those without. There was a non-significant correlation between ACE2 level and mRss (p = 0.16). ConclusionsSerum ACE2 levels are decreased in patients with SSc and related to telangiectasias and the use of cyclophosphamide.

Effect of SARS-CoV-2 spike protein exposure on ACE2 and interleukin 6 productions in human adipocytes: An in-vitro study.

Since adipocytes play a crucial role in pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to their interaction with angiotensin-converting enzyme 2 (ACE2) and interleukin 6 (IL-6), obesity is associated with an increased risk of coronavirus disease 2019 (COVID-19) mortality. Discovery of ACE2 as a SARS-CoV-2 receptor raises a controversy about whether to use ACE inhibitors (ACEIs) could be an optional therapy to prevent cytokine storms. Studies assessing the expressions of ACE2 and IL-6 upon exposure to SARS-CoV-2 is therefore important as a basis for therapeutical trials in the future. The aim of this study was to determine the effect of SARS-CoV-2 spike protein exposure on the production of ACE2 and IL-6 in adipocyte cells. Adipocytes were collected from abdominal adipose tissues of healthy and obese 45-year-old male donor having neither a history of SARS-CoV-2 infection nor COVID-19 vaccination. After being stained using the oil red O protocol, the viable adipocytes were then exposed to S1 subunit of SARS-CoV-2 spike protein. The levels of ACE2 and IL-6 were then examined using the enzyme-linked immunosorbent assay (ELISA). The results showed significant increase of ACE2 (90.22 µg/mL) and IL-6 level (60.01 µg/mL) in human adipocytes upon exposure compared to unexposed control cells (ACE2 13.33 µg/mL; IL-6 21.33 µg/mL), both comparisons had p<0.001). This study provides insight into the basic mechanism of severe COVID-19 symptoms in obese patients and provides a basic information of the potential of ACE inhibitors as an optional therapy for COVID-19 patients with obesity.

Effect of renin angiotensin blockers on angiotensin converting enzyme 2 level in cardiovascular patients

BackgroundRenin–angiotensin–aldosterone system (RAAS) is hypothesized to be in the center of COVID pathophysiology as the angiotensin converting enzyme 2 (ACE2) represents the main entrance of the virus, thus there is a need to address the effect of chronic use of RAAS blockers, as in case of treatment of cardiovascular diseases, on the expression of ACE2. Accordingly, this study aimed to clarify the effect of ACE inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) on ACE2 and to assess the correlation between ACE2 and several anthropometric and clinic-pathological factors.MethodsA total of 40 healthy controls and 60 Egyptian patients suffering from chronic cardiovascular diseases were enrolled in this study. Patients were divided into 40 patients treated with ACEIs and 20 patients treated with ARBs. Serum ACE2 levels were assessed by ELISA.ResultsAssessment of serum ACE2 level in different groups showed a significant difference between ACEIs and healthy groups and ACEIs and ARBs group, while there was no difference between ARBs and healthy. Multivariate analysis using ACE2 level as constant and age, female sex, ACEIs use and myocardial infarction (MI) showed that there was a significant effect of female sex and ACEIs use on ACE2 level with no effect of age, MI and diabetes.ConclusionACE2 levels varied between ACEIs and ARBs. It tends to be lower in ACEIs group and there is a strong positive association between ACE2 level and the female sex. This needs to be considered in Future studies to further understand the relationship between gender, sex hormones and ACE2 level.Trial registrationRetrospectively registered ClinicalTrials.gov ID: NCT05418361 (June 2022).Graphical abstract

Intronic Variants of the Angiotensin-Converting Enzyme 2 Gene Modulate Plasma ACE2 Levels and Possibly Confer Protection against Severe COVID-19.

Membrane-bound angiotensin-converting enzyme 2 (ACE2) receptor acts as the entry point for the novel coronavirus, SARS-CoV-2. Polymorphisms in the ACE2 gene may alter viral binding, regulate the expression of ACE2, and thus, affect disease severity. In this study, 68 COVID-19 patients with varying degrees of severity and 40 healthy controls were enrolled. The genetic landscape of the ACE2 gene was explored by whole exome sequencing of 29 individuals, and specific regions of ACE2 were analyzed for the rest of the participants via PCR, followed by barcode-tagged sequencing. The mean soluble ACE2 level in the plasma of healthy controls and patients did not vary significantly but was higher in the patient group (3.77 ± 1.55 ng/mL vs. 3.94 ± 1.42 ng/mL). Analysis of exon 1, exon 2, and exon 8 of the ACE2 gene revealed that these regions are highly conserved in our population. Investigation of exon 11 and its flanking intronic region revealed that deletions in a stretch of 18T nucleotides in the noncoding region significantly decrease ACE2 levels in plasma, as individuals harboring wild-type variants had higher plasma ACE2 levels compared to those harboring T1del, T2del, and T3del variants. However, the intronic variants were not found to be significantly associated with disease severity.

Soluble ACE2 as a Risk or Prognostic Factor in COVID-19 Patients: A Cross-sectional Study.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel severe acute respiratory syndrome coronavirus. The first known receptor for this virus in the human body is angiotensin-converting enzyme 2 (ACE2), the same receptor for the SARS virus. Methods: A total of 38 hospitalized adult (18 years) patients with laboratory or clinically confirmed coronavirus disease 2019 (COVID-19) were identified in the infectious disease ward of Tehran Imam Khomeini hospital complex in this single-center cross-sectional study. A blood sample was taken at the time of hospitalization and a second one was taken 48 hours later. Blood samples are kept frozen at -80 degrees Celsius. After the complete collection of samples, the ACE2 level of the samples was measured using a serum sACE2 detection ELISA kit. The data were analyzed using SPSS v26. P value of 0.05 was considered statistically significant. An analysis of covariance was performed to examine the mean differences in day 7 serum ACE2 concentration among the 2 groups after adjusting for the baseline serum ACE2 concentration. The 1-way multivariate analysis of variance was used to determine whether there were any differences between independent groups (mechanical ventilation yes/no) on serum ACE2 levels at 3 different times. Results: The mean age of patients was 64.13 ± 16.49 years, 21 patients (55.3%) were men, 16 patients (42%) were polymerase chain reaction test positive, and 15 patients (39.5%) died. A total of 35 individuals (92.1%) had chest computed tomography images that indicated lung involvement. A comparison of the 2 groups of patients who died and were discharged revealed that serum ACE2 at the first (p=0.033) and third (7th day) measurements were statistically different (p=0.026). Patients had a mean of serum ACE2. The results indicated that the day 7 serum ACE2 concentration did significantly differ between the 2 groups after controlling for the baseline serum ACE2 concentration (p=0.023). The model explained about 73.61% of the variance in the 7-day serum ACE2 concentration. Specifically, after adjusting for the baseline concentration, survived patients had the lowest level of serum ACE2 concentration (1 ± 0.65) on the 7th day compared with the deceased patient group (2.83 ± 1.12). Conclusion: Soluble ACE2 in the serum of COVID-19 patients who died, later on, was significantly higher than the discharged patients when the samples were taken seven days after admission. It is suggested that serum soluble ACE2 level could be used as a prognostic factor for COVID-19 patients' outcomes and also their need for mechanical ventilation.

The Impact of Angiotensin Converting Enzyme-2 (ACE-2) on Bone Remodeling Marker Osteoprotegerin (OPG) in Post-COVID-19 Iraqi Patients.

Introduction As COVID-19affects human genes in several types of peripheral tissue, numerous disorders occur after recovery. The virus enters host cells via angiotensin-converting enzyme-2 (ACE-2) receptors that affect bone remodeling, leading to osteopenia or osteoporosis, which is characterized by low bone mineral density (BMD). The adult skeleton undergoes about 10% remodeling annually, which is crucial for preventing fatigue damage and preserving calcium homeostasis. An imbalance in the rates of bone production and resorption causes bone loss. Osteoprotegerin (OPG) is one of the regulators involved in the bone remodeling mechanism, it decreases the activity of NF-B receptors that activates the receptor activators of NF-B ligand (RANKL) pathway, which maintains the bone homeostasis balance. This study aims to find out the disruption of bone homeostasis balance in Iraqi post-COVID-19 patients. Materials and methods It is a case-control study that includes 130 Iraqi subjects enrolled. They were divided into two groups - the first group consisted of 80 post-COVID-19 infection patients, while the second group consisted of 50 who were not infected with COVID-19. Also, the levels of ACE-2 and OPGwere measured in the serum by the ELISA technique. The BMD was measuredby the DEXA scan technique. Results This study found that there is an effect of coronavirus infection on the bone strength measured by the Mean of the OPGlevel, which was found to be highly significant in the serum of post-COVID-19 patients when compared with non-COVID-19 subjects (P-value = 0.001), but the Mean of ACE-2 level was statistically non-significant between the two groups (P-value = 0.13). Also, the BMD of post-COVID-19 patients that was measured by DEXA scan had a statistically highly significant T-score% between the two groups. Conclusion The current study found that there was an effect of COVID-19 on the bone remodeling mechanism, which may be causing osteopenia or osteoporosis for Iraqi subjects enrolled in the current study. Also, analyzing the OPG level in the serum could be helpful in predicting low BMD.

A Systematic Review Approach in Understanding the COVID-19 Mechanism in Diabetes and its Progression to Diabetic Microvascular Complications

Introduction: In uncontrolled hyperglycemia, lungs, tongue, oropharyngeal and nasopharyngeal airways having increased glycosylated angiotensin-converting enzyme 2 (ACE2) can serve as good viral binding sites for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to a greater tendency and considerable risk of prolonged life-threatening disease. This review was written with the objective to extract the recent advances, updates, and discoveries about the effects of coronavirus disease-2019 (COVID-19) on patients with diabetes and its microvascular complications. It was further written with the aim to discuss the current state of knowledge that has not yet been confirmed or unconfirmed, leading to various debatable issues about COVID-19-associated with microvascular complications in diabetes mellitus. Materials and Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched scientific sites related to our review article such as Web of Science, Embase, PubMed, Scopus, Google Scholar, and MEDLINE of last nearly two and half years. Results: The individuals who are suffering from type 2 diabetes mellitus experience more organ damage by SARS-Cov-2 due to cytokine storm. The pro-inflammatory state, lower primary immune system response, and increased ACE2 level with dysregulation of vascular function and the prothrombic state in patients with diabetes may increase the vulnerability for COVID-19 and worsened prognosis. The patients have reduced prognosis leading to microvascular complications such as diabetic nephropathy, neuropathy and retinopathy. In diabetes retinopathy, it induces the changes in the vasculature of the retinal veins. These viruses can directly affect the nervous tissue and/or can indirectly via activating the immune system-mediated mechanisms leading to diabetic neuropathy as well. Conclusions and Implications: During the cytokine storm the amount of D-dimer in the serum gets significantly increased, due to increased activating plasmin at the early stage of inflammation. Uncontrolled hyperglycemia leads to diabetic complications leading to increased mortality rate in patients with COVID-19. Thus, diabetes and its associated microvascular complications may lead to the severity and mortality in the patients with COVID-19. More of clinical practice and further studies should be implicated through this review article. Laboratory findings and clinical records are of much help in patients with diabetes and COVID-19. Worldwide studies from different countries apart from China should be considered to reach a conclusion about the conditions of patients with diabetes and microvasculature complications around the world.

Metainflammation in COVID-19

A new coronavirus pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been on the rise. This virus is fatal for broad groups of populations, including elderly, men, and patients with comorbidities among which obesity is a possible risk factor. The pathophysiologic connections between obesity/metainflammation and COVID-19 may be directly related to increasing soluble ACE2 (angiotensin-converting enzyme 2) levels which potentiate the viral entrance into the host cells, or indirectly related to dysregulation of immune system, microvascular injury and hypercoagulability. The SARS-CoV-2 S-glycoprotein interacts mainly with ACE2 or possibly DPP4 receptors to enter into the host cells. The host proteases, especially TMPRSS2 (transmembrane protease serine 2), support the fusion process and virus entry. While membranous ACE2 is considered a port of entry to the cell for SARSCoV- 2, it seems that soluble ACE2 retains its virus binding capability and enhances its entry into the cells. Interestingly, ACE2 on cell membrane may have protective roles by diminishing cytokine storm-related injuries to the organs. Applying medications that can reduce soluble ACE2 levels, antagonizing TMPRSS2 or blocking DPP4 can improve the outcomes of COVID-19. Metformin and statins through immunomodulatory activities, Orlistat by reducing viral replication, and thiazolidinediones by upregulating ACE2 expression have potential beneficial effects against COVID-19. However, the combination of dipeptidyl peptidase-4 (DPP4) inhibitors and spironolactone/ eplerenone seems to be more effective by reducing soluble ACE2 level, antagonizing TMPRSS2, maintaining ACE2 on cell membrane and reducing risk of viral entry into the cells.

An improved Fuzzy based GWO algorithm for predicting the potential host receptor of COVID-19 infection

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has infected millions worldwide. SARS-CoV-2 spike protein uses Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2) for entering and fusing the host cell membrane. However, interaction with spike protein receptors and protease processing are not the only factors determining coronaviruses’ entry. Several proteases mediate the entry of SARS-CoV-2 virus into the host cell. Identifying receptor factors helps understand tropism, transmission, and pathogenesis of COVID-19 infection in humans. The paper aims to identify novel viral receptor or membrane proteins that are transcriptionally and biologically similar to ACE2 and TMPRSS2 through a fuzzy clustering technique that employs the Grey wolf optimizer (GWO) algorithm for finding the optimal cluster center. The exploratory and exploitation capability of GWO algorithm is improved by hybridizing mutation and crossover operators of the evolutionary algorithm. Also, the genetic diversity of the grey wolf population is enhanced by eliminating weak individuals from the population. The proposed clustering algorithm’s effectiveness is shown by detecting novel viral receptors and membrane proteins associated with the pathogenesis of SARS-CoV-2 infection. The expression profiles of ACE2 protein and its co-receptor factor are analyzed and compared with single-cell transcriptomics profiling using the Seurat R toolkit, mass spectrometry (MS), and immunohistochemistry (IHC). Our advanced clustering method infers that cell that expresses high ACE2 level are more affected by SARS-CoV-infection. So, SARS-CoV-2 virus affects lung, intestine, testis, heart, kidney, and liver more severely than brain, bone marrow, skin, spleen, etc.We have identified 58 novel viral receptors and 816 membrane proteins, and their role in the pathogenicity mechanism of SARS-CoV-2 infection has been studied. Besides, our study confirmed that Neuropilins (NRP1), G protein-coupled receptor 78 (GPR78), C-type lectin domain family 4 member M (CLEC4M), Kringle containing transmembrane protein 1 (KREMEN1), Asialoglycoprotein receptor 1 (ASGR1), A Disintegrin and metalloprotease 17 (ADAM17), Furin, Neuregulin-1,(NRG1), Basigin or CD147 and Poliovirus receptor (PVR) are the potential co-receptors of SARS-CoV-2 virus. A significant finding is that heparin derivative glycosaminoglycans could block the replication of SARS-CoV-2 virus inside the host cytoplasm. The membrane protein N-Deacetylase/N-Sulfotransferase-2 (NDST2), Extostosin protein (EXT1, EXT2, and EXT3), Glucuronic acid epimerase (GLCE), and Xylosyltransferase I, II (XYLT1, XYLT2) could act as the therapeutic target for inhibiting the spread of SARS-CoV-2 infection. Drugs such as carboplatin and gemcitabine are effective in such situations.

Variations in Cell Surface ACE2 Levels Alter Direct Binding of SARS-CoV-2 Spike Protein and Viral Infectivity: Implications for Measuring Spike Protein Interactions with Animal ACE2 Orthologs.

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), the most severe pandemic in a century. The virus gains access to host cells when the viral spike protein (S-protein) binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2). Studies have attempted to understand SARS-CoV-2 S-protein interactions with vertebrate orthologs of ACE2 by expressing ACE2 orthologs in mammalian cells and measuring viral infection or S-protein binding. Often, these cells only transiently express ACE2 proteins, and the levels of ACE2 at the cell surface are not quantified. Here, we describe a cell-based assay that uses stably transfected cells expressing ACE2 proteins in a bicistronic vector with an easy-to-quantify reporter protein, Thy1.1. We found that both the binding of the S-protein receptor-binding domain (RBD) and infection with a SARS-CoV-2 pseudovirus are proportional to the amount of human ACE2 expressed at the cell surface, which can be inferred by quantifying the level of Thy1.1. We also compared different ACE2 orthologs, which were expressed in stably transfected cells expressing equivalent levels of Thy1.1. When ranked for either viral infectivity or RBD binding, mouse ACE2 had a weak to undetectable affinity for S-protein, while human ACE2 had the highest level detected, and feline ACE2 had an intermediate phenotype. The generation of stably transfected cells whose ACE2 level can be normalized for cross-ortholog comparisons allows us to create a reusable cellular library useful for measuring emerging SARS-CoV-2 variants’ abilities to potentially infect different animals.IMPORTANCE SARS-CoV-2 is a zoonotic virus responsible for the worst global pandemic in a century. An understanding of how the virus can infect other vertebrate species is important for controlling viral spread and understanding the natural history of the virus. Here, we describe a method to generate cells stably expressing different orthologs of ACE2, the receptor for SARS-CoV-2, on the surface of a human cell line. We find that both the binding of the viral spike protein receptor-binding domain (RBD) and infection of cells with a SARS-CoV-2 pseudovirus are proportional to the ACE2 levels at the cell surface. This method will allow the creation of a library of stably transfected cells expressing similar levels of different vertebrate ACE2 orthologs, which can be used repeatedly for identifying vertebrate species that may be susceptible to infection with SARS-CoV-2 and its many variants.

Spike-mediated ACE2 down-regulation was involved in the pathogenesis of SARS-CoV-2 infection

The ongoing global pandemic of Coronavirus disease 2019 (COVID-19) poses a serious threat to human health, with patients reportedly suffering from thrombus, vascular injury and coagulation in addition to acute and diffuse lung injury and respiratory diseases. Angiotensin converting enzyme 2 (ACE2) as the receptor for SARS-CoV-2 entry, is also an important regulator of renin-angiotensin system (RAS) homeostasis, which plays an unsettled role in the pathogenesis of COVID-19. Here, we demonstrated that SARS-CoV-2 Spike protein activated intracellular signals to degrade ACE2 mRNA. The decrease of ACE2 and higher level of angiotensin (Ang) II were verified in COVID-19 patients. High dose of Ang II induced pulmonary artery endothelial cell death in vitro, which was also observed in the lung of COVID-19 patients. Our finding indicates that the downregulation of ACE2 potentially links COVID-19 to the imbalance of RAS.

Зміни експресії та локалізації ангіотензинперетворювального ензиму-2 при гострій експериментальній бронхопневмонії

Coronavirus (SARS-CoV-2) enters the cell by binding to a transmembrane glycoprotein, angiotensin-converting enzyme-2 (ACE2), which is expressed on the surface of the bronchial and alveolar epithelium. In this regard, the aim of this study was to determine changes in the content and characteristics of tissue localization of ACE2 in the model of acute bronchopulmonary inflammation. The latter was modeled by endotracheal injection of a foreign body (Capron thread) and a solution of lipopolysaccharide (LPS; 50 μl at a dose of 12.5 mg/kg) against the background of systemic administration of LPS for two days before surgery (250 mg/ kg). ACE2 localization and quantity were evaluated by immunohistochemical and western blot assays with the use of a specific monoclonal antibody. The experiment reproduced acute exudative-hemorrhagic bronchopneumonia with the development of diffuse progressive pulmonary fibrosis with lethality in 36% of animals. Acute exudative inflammation was accompanied by complete inhibition of ACE2 expression in bronchial epitheliocytes and its significant decrease in alveolocytes type II. With the development of the proliferative stage of bronchopneumonia, the level of ACE2 was restored, subsequently remaining without significant changes. The obtained experimental data suggest the existence of a relationship between the features of quantitative changes in the ACE2 level in the bronchopulmonary epithelium and the undulating course of the inflammatory process during SARS-CoV-2 infection.

Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer's Disease.

An imbalance in the renin-angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer's disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n = 121; 19-95 years age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, United Kingdom, and AD and age-matched controls (n = 60) from the South West Dementia Brain Bank, University of Bristol, United Kingdom, stratified according to Braak tangle stage (BS): 0-II, III-IV (intermediate disease), and V-VI (end-stage disease). ACE-1 and ACE-2 enzyme activity were measured using fluorogenic peptide activity assays. ACE-1, ACE-2, and Ang-II protein level were measured by enzyme-linked immunosorbent assay (ELISA). In both regions, ACE-1 protein and Ang-II levels correlated positively with age whereas ACE-1 enzyme activity was inversely related to age. ACE-1 protein correlated positively with Ang-II, whilst ACE-1 activity correlated inversely with Ang-II in normal aging. ACE-1 enzyme activity was elevated at an early/intermediate stage, BS III-IV compared to BS 0-II in the temporal cortex in AD. ACE-2 protein and enzyme activity were unchanged with aging and in AD. In conclusion, ACE-1 activity is induced in the early stages of AD independently from normal physiological age-related changes in ACE-1 protein.

Angiotensin-converting enzyme 2 inhibits inflammation and apoptosis in high glucose-stimulated microvascular endothelial cell damage by regulating the JAK2/STAT3 signaling pathway

ABSTRACT Mounting evidence supports that angiotensin-converting enzyme 2 (ACE2) may exert a vital function in multiple complications induced by diabetes. The aim of this research was to verify the function of ACE2 in diabetic angiopathy (DA). In our study, it was revealed that high glucose (HG) treatment impeded cell proliferation and induced cell apoptosis. Moreover, ACE2 level was reduced in HG-stimulated HMEC-1 cells. Functional assays demonstrated that ACE2 addition promoted cell viability, suppressed apoptosis, oxidative stress, ROS generation, and inflammation in HG-stimulated HMEC-1 cells. Furthermore, the activation of the JAK2/STAT3 pathway induced by HG was impeded by overexpression of ACE2. Besides, JAK2/STAT3 pathway inhibitor AG490 reversed the changes of cell viability, apoptosis, oxidative stress, and inflammation caused by ACE2 deletion in HG-treated HMEC-1 cells. In sum, our findings highlighted that ACE2 promoted the viability and restrained the oxidative stress, inflammation, and apoptosis in HG-induced microvascular endothelial cells (VECs) injury via regulating the JAK2/STAT3 pathway, suggesting ACE2 might be a potential therapeutic target for DA treatment.

Serum ACE2 Level is Associated With Severe SARS-CoV-2 Infection: A Cross-Sectional Observational Study.

Objectives:Angiotensin-converting enzyme 2 (ACE2) represents the primary receptor for SARS-CoV-2 to enter endothelial cells, causing coronavirus disease of 2019 (COVID-19). In this study, we investigate the association between circulating ACE2 levels with the severity of COVID-19.Methods:Serum ACE2 levels were measured in 144 COVID-19-positive subjects at hospital admission, and 123 COVID-19-negative control subjects. The association between ACE2 and clinical outcomes was analyzed.Results:About 144 COVID-19 patients and 123 healthy controls data were analyzed, the mean age of patients was 62 years and 50% of them were males. The mean age of the control group was 55 years and 63% were males. ACE-II level was measured and compared between COVID-19 patients and controls and revealed no significant differences (P > .05). ACE-II level was measured in COVID-19 patients and compared between different patient’s subgroups, ACE II level was not dependent on gender, smoking, ACE intake, or comorbidities (P > .05), and was significantly correlated with cardiovascular diseases (CVS) (P-value = .046) ICU admission (P-value = .0007) and Death (P-value = .0082).Conclusion:There was no significant difference between the COVID-19 and Control group, however, ACE2 serum level was significantly higher in patients with COVID-19 who were critically ill or non-survivors, its increased level is also associated with length of stay. Elevated ACE2 level is associated with the severity of COVID-19 disease, and it has the potential to be a predictor of the severity of the disease.

Large Screening Identifies ACE2 Positively Correlates With NF-κB Signaling Activity and Targeting NF-κB Signaling Drugs Suppress ACE2 Levels.

Coronaviruses SARS-CoV-2 infected more than 156 million people and caused over 3 million death in the whole world, therefore a better understanding of the underlying pathogenic mechanism and the searching for more effective treatments were urgently needed. Angiotensin-converting enzyme 2 (ACE2) was the receptor for SARS-CoV-2 infection. In this study, we found that ACE2 was an interferon-stimulated gene (ISG) in human cell lines. By performing an ISG library screening, we found that ACE2 levels were positively regulated by multiple ISGs. Interestingly, ACE2 levels were highly correlated with ISGs-induced NF-κB activities, but not IFNβ levels. Furthermore, using an approved clinical durgs library, we found two clinical drugs, Cepharanthine and Glucosamine, significantly inhibited ACE2 level, IFNβ level, and NF-κB signaling downstream TNFα and IL6 levels. Our finding suggested the possible inhibitory effects of Cepharanthine and Glucosamine during SARS-CoV-2 infection and the subsequent inflammatory cytokine storm.

Lack of Association Between ACE2 Expression and Serum Testosterone Concentrations in Peripheral Mononuclear Cells in Males

Background: Male sex is a risk factor for developing severe COVID-19 illness, hospitalization, and mortality. It is possible that the male sex hormone, testosterone, contributes to the morbidity from COVID-19. SARS-CoV2 viruses use cell membrane protein Angiotensin-Converting Enzyme 2 (ACE2) receptor and undergo S protein priming by the Type II Transmembrane Serine Protease (TMPRSS2) to enter the cells. Hence, the expression level of ACE2 and TMPRSS2 may affect disease susceptibility and possible severity. TMPRSS2 is regulated by the androgen receptor. We, therefore, examined if an association exists between serum testosterone concentrations and ACE2 or TMPRSS2 expression level in men. Methods: We analyzed fasting serum samples and peripheral blood mononuclear cells (MNC) from 42 men. Total and free testosterone and estradiol were measured by liquid chromatography/equilibrium dialysis. Sex hormone binding globulin (SHBG) was measured by chemiluminescence. mRNA was prepared from MNC. Quantitative RT-PCR was conducted using commercially available, pre-designed TaqMan primers and probes targeting ACE2. The ACE2 relative level was calculated after normalization to beta Actin and GAPDH, with lowest ACE2 level being set to 1. Results: Subjects’ age ranged from 20 to 65 years. Type 2 diabetes was present in 74% of the men and the mean HbA1 was 7.2±1.6% (mean ± S.D.). Fifteen subjects had subnormal free testosterone (<50 pg/ml). Compared to the 27 subjects with normal free testosterone, they were older (49±12 vs 40±13 years, p=0.03) but had similar BMI (36±10, 35±10 kg/m2, p=0.71). As expected, they had lower total testosterone (Median [25th, 75th percentile]; 222 [171-266] vs 431 [335, 618] ng/dl, p<0.001) and free testosterone concentrations (39 [21, 44] vs 72 [59, 92], p<0.001). Total estradiol was also lower in this group (19±1 vs 29±13 pg/ml, p=0.03) but free estradiol (0.44±0.33 vs 0.56±0.34 pg/ml, p=0.44) and SHBG (27 [19, 33] vs 30 [21, 39] nmol/L, p=0.52) were similar. Quantitative PCR data showed there was a large inter-individual variation of ACE2 expression level, up to 15-fold difference. Average ACE2 level did not differ between subnormal and normal testosterone groups (3.4 [2.7, 5.0] vs 3.9 [2.5, 5.7] arbitrary units). ACE2 expression was not related to free testosterone (r=0.11), free estradiol (r=0.18) or sex hormone binding globulin (r=0.15) on linear regression analyses (p>0.30 for all). ACE2 expression was also not related to age (r= -0.15, p=0.34), BMI (r= -0.2, p=0.23) or presence of diabetes. We were not able to detect a significant expression of TMPRSS2 in MNC. Conclusion: Our results do not support a role for testosterone or estradiol as regulators of ACE2 expression in peripheral blood MNC in males.

Effects of Pennyroyal (Mentha pulegium L.) on Angiotensin Converting Enzyme-2 (ACE-2) and Antioxidant Parameters in Rabbits

Many studies have been conducted on medicinal aromatic plants in recent years. Alternative medicine particularly comes to the fore as an alternative to the use of synthetic agents. The antioxidant, anti-inflammatory, antimicrobial and antiviral effects of phenolic compounds, especially in the structure of aromatic plants, are known. Among those well-known aromatic plants, Pennyroyal (Mentha pulegium L.) is known to contain a large amount of phenolic compounds. In our study, by taking these effects of phenolic compounds into consideration, the effectiveness of pennyroyal on antioxidant parameters and Angiotensin-converting enzyme 2 (ACE2) which is the receptor that Covid-19 binds, and that has many important functions in the organism, was evaluated. A total of 15 New Zealand rabbits were used in the study. The animals were divided into three experimental groups with 5 rabbits in each group. While no Pennyroyal was added to the control group, 0.1% and 0.2% were added to the diets for the other groups. All groups were fed ad-libitum. On the 14th day of the experiment, serum ACE2, GSH and MDA levels were determined with blood taken from the ears of the rabbits. According to the analysis results, while a decrease in ACE2 and MDA levels was determined in the groups which were given 0.1% and 0.2% Pennyroyal compared to the control group, a significant increase was observed in the GSH level. As a result, determining the antioxidant effect of Pennyroyal as well as the effect of decreasing the serum ACE2 level revealed the need for more research to fully explain the effectiveness of aromatic plants in combating Covid-19.

Apigetrin inhibits cytotoxicity and dysregulation of ACE2, IL1α and TGFβ expression induced by recombinant spike protein of SARS-CoV-2

SARS-CoV-2 virus is a novel coronavirus that was first identified in Wuhan, China in December 2019 and has caused an ongoing global health crisis. It has been a worldwide focus in research to understand viral pathogenesis and discover effective therapies. SARS-CoV-2 belongs to the same genus as the viruses responsible for Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS). Spike protein (SP) on SARS-CoV-2 plays a key role in the pathogenesis of SARS-CoV-2. The virus enters human cells via the binding of SP to the angiotensin-converting enzyme 2 (ACE2) on human cells. The binding of SP inhibits ACE2 function by reducing formation of angiotensin-(1-7), a compound that has inhibitory effects on inflammation. In addition, SARS-CoV-2 induces excessive proinflammatory cytokine production through various other signaling pathways such as the NFκB and NLRP3 inflammasome pathways. Previous evidence showed that apigenin (APG), a plant phenolic compound, can bind to SP. However, whether or not apigetrin (APT), the glucoside conjugate of APG, can protect human cells against cell injury caused by SARS-CoV-2 is still unknown. Studies have shown that SARS-CoV-2 induced dysregulation of host cell ACE2 expression is one of the major pathophysiological factors of COVID-19 infection. Our current study demonstrated that recombinant SP significantly reduced ACE2 level in human neuronal cells in a dose dependent manner using ELISA assay. Interestingly, APT reversed the SP induced ACE2 downregulation in these cells. In this study, the effect of SP on cell proliferation and immune regulation was also investigated. Using MTT and LDH assays, I discovered that SP had a cytotoxic effect on these cells and significantly inhibited cell proliferation. This cytotoxic effect was mitigated by adding APT treatment. Furthermore, APT reduced SP induced cytokine production such as IL1α and TGFβ . In sum, my study demonstrated that APT inhibited SARS-CoV-2 SP induced dysregulation of human cells and reduced its cytotoxic effects on cells. APT significantly upregulated ACE2 expression and inhibited the production of cytokines IL1α and TGFβ in the cells treated with SP. My study indicated that APT has potential to be a novel therapy for COVID-19 infection. More experiments to further elucidate molecular mechanisms of how APT modulates pathological effect of SP with different in vitro models including other human cell lines and in vivo animal models are currently being performed.

SARS-CoV-2 cell receptor gene ACE2 -mediated immunomodulation in breast cancer subtypes

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has impacted the world severely. The binding of the SARS-CoV-2 virus to the angiotensin-converting enzyme 2 (ACE2) and its intake by the host cell is a necessary step for infection. ACE2 has garnered widespread therapeutic possibility as it is entry/interactive point for SARS-CoV-2, responsible for coronavirus disease 2019 (COVID-19) pandemic and providing a critical regulator for immune modulation in various disease. Patients with suffering from cancer always being on the verge of being immune compromised therefore gaining knowledge about how SARS-CoV-2 viruses affecting immune cells in human cancers will provides us new opportunities for preventing or treating virus-associated cancers. Despite COVID-19 pandemic got center stage at present time, however very little research being explores, which increase our knowledge in context with how SARS-CoV-2 infection affect cancer a cellular level. Therefore, in light of the ACE-2 as an important contributor of COVID-19 global, we analyzed correlation between ACE2 and tumor immune infiltration (TIL) level and the type markers of immune cells were investigated in breast cancer subtypes by using TIMER database. Our findings shed light on the immunomodulatory role of ACE2 in the luminal A subtype which may play crucial role in imparting therapeutic resistance in this cancer subtype.