Serum Angiotensin-converting Enzyme 2 Research Articles

Serum AXL is a potential molecular marker for predicting COVID-19 progression.

The severity, symptoms, and outcome of COVID-19 is thought to be closely linked to how the virus enters host cells. This process involves the key roles of angiotensin-converting enzyme 2 (ACE2) and the Tyrosine protein kinase receptor UFO (AXL) receptors. However, there is limited research on the circulating levels of ACE2 and AXL and their implications in COVID-19. A control group of 71 uninfected individuals was also included in the study. According to the Guidance for Corona Virus Disease 2019 (10th edition), a cohort of 358 COVID-19 patients were categorized into non-severe and severe cases. Serum ACE2/AXL levels in COVID-19 patients were detected by enzyme-linked immunosorbent assay (ELISA) at different time points post-COVID-19 infection, including days 0-7, 8-15, 31-179 and >180 days. Serum SARS-CoV-2 IgG/IgM antibodies in COVID-19 patients at the same intervals were assessed by using an iFlash 3000 Chemiluminescence Immunoassay Analyzer. The receiver operating characteristic (ROC) curves were used to assess the diagnostic value of the biological markers, and the association between laboratory parameters and illness progression were explored. Compared with the uninfected group, the levels of ACE2 and AXL in the COVID-19 group were decreased, and the SARS-COV-2 IgG level was increased. AXL (AUC = 0.774) demonstrated a stronger predictive ability for COVID-19 than ACE2. In the first week after infection, only the level of AXL was statistically different between severe group and non-severe group. After first week, the levels of ACE2 and AXL were different in two groups. Moreover, in severe COVID-19 cases, the serum ACE2, AXL, and SARS-COV-2 IgM levels reached a peak during days 8-15 before declining, whereas serum SARS-COV-2 IgG levels continued to rise, reaching a peak at day 31-180 days before decreasing. In addition, the AXL level continued to decrease and the SARS-COV-2 IgG level continued to increase in the infected group after 180 days compared to the uninfected group. The levels of serum ACE2 and AXL correlate with COVID-19 severity. However, AXL can also provide early warning of clinical deterioration in the first week after infection. AXL appears to be a superior potential molecular marker for predicting COVID-19 progression.

Prognostic properties of biomarkers in COVID-19 infection and concomitant chronic coronary syndromes

Background. The novel coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become an unprecedented challenge for the health care system and has taken a leading position among infectious diseases due to the rapid spread and development of complications from various body systems. The problem of cardiac comorbidity in COVID-19 has several aspects: the impact of concomitant cardiovascular diseases on the incidence of a new viral infection, its severity and risk of mortality, as well as possible side effects of a number of drugs traditionally used to treat certain types of cardiovascular diseases. SARS-CoV-2 is not only a pneumonia pathogen, but also causes serious systemic consequences. Patients with cardiovascular diseases and risk factors for cardiovascular complications, such as hypertension and coronary heart disease, are more exposed to fatal consequences of COVID-19. In addition, a significant proportion of patients develop COVID-associated myocardial injury, which significantly increases the risk of in-hospital mortality. The purpose of the study was to investigate the prognostic role of individual biomarkers in patients with COVID-19-associated pneumonia on the background of chronic coronary syndromes. Materials and methods. This study was defined as an open-label, non-randomized, controlled, comparative one in parallel groups. 124 patients with COVID-19-associated pneumonia were selected upon admission, including 92 participants with a history of chronic coronary syndromes. Results. The study showed that elevated levels of biomarkers such as proinflammatory cytokine interleukin-6, iron-storage protein ferritin, serum angiotensin-converting enzyme-2, ketone body beta-hydroxybutyric acid, and fibrin breakdown product D-dimer may be associated with a more severe course of pneumonia caused by COVID-19 infection. Thus, these biomarkers had good prognostic value in predicting severe disease and death in patients with chronic coronary syndromes during hospitalization. Conclusions. The study confirms that an increase in the level of proinflammatory biomarkers is a predictor for the development of a severe coronavirus infection.

Differences in vascular endothelial function and serum proteome between obese people with phlegm-dampness constitution and balanced constitution.

To evaluate the extent of vascular endothelial dysfunction and preliminary identify serum protein biomarkers associated with obese individuals at risk for cardiovascular disease (CVD). Fifteen obese volunteers with the phlegm-dampness constitution or balanced constitution were recruited for this study respectively. The clinical baseline data was collected, and the vascular endothelial function was evaluated using the EndoPATTM. Blood samples were collected for the serum proteome analysis. The differences in the serum protein expression levels between the two groups were detected and the protein interaction network analysis, correlation analysis, receiver operating characteristic (ROC) curve analysis, and random forest model investigation were conducted. There were no statistical differences found in the baseline data. For vascular endothelial function, the reactive hyperemia index (RHI) of the phlegm-dampness constitution obese group was significantly lower than that of the balanced constitution obese group (1.46 ± 0.30 vs 2.82 ± 0.78, P < 0.0001), indicating vascular endothelial dysfunction. There are 66 differentially expressed serum proteins between the two groups. apolipoprotein A2 (ApoA2), angiotensin-converting enzyme 2 (ACE-2), interleukin-33 (IL-33), and forkhead box P3 (FoxP3) showed significant differences and area under curve values of their ROC curves were greater than 0.7 and correlated significantly with RHI. Vascular endothelial dysfunction was present in the phlegm-dampness constitution obese group. Thus, alterations in the expression levels of key serum proteins, including ApoA2, ACE-2, IL-33, and FoxP3 could serve as potential biomarkers in the obese population at risk of CVD.

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.

Nerve Growth Factor and Angiotensin Converting Enzyme 2 Levels in Children with Neurodevelopmental Disorders

Objective Neurodevelopmental disorders (NDDs) are the most common psychiatric disorders in childhood, and there are many factors in their etiology. In recent years, many biomarkers have been studied to elucidate the etiology of these disorders. In this study, it was aimed to investigate the levels of nerve growth factor (NGF) and angiotensin converting enzyme 2 (ACE2) in attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Methods The study included 74 children with NDDs (the number of patients in ADHD, ASD and ID groups were 24, 25 and 25 respectively) and 30 healthy controls (HCs). Serum NGF and ACE2 levels were studied with ELISA kits, also complete blood count (CBC), levels of fasting glucose and serum lipids were assessed. Results ACE2 levels were found to be lower in NDD group than HCs in girls. In boys with ASD, triglyceride levels were significantly higher than other groups. Also a positive correlation was found between ACE2 and NGF levels when all sample assessed together. Conclusions This study is a premise for investigating ACE2 and NGF in NDDs. The role of these markers in ADHD, ASD, ID and other NDDs and their associations with gender should be assessed by studies in which both larger sample groups and more disorders.

Analysis between ABO blood group and clinical outcomes in COVID-19 patients and the potential mediating role of ACE2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most common coronavirus that causes large-scale infections worldwide. Currently, several studies have shown that the ABO blood group is associated with coronavirus disease 2019 (COVID-19) infection and some studies have also suggested that the infection of COVID-19 may be closely related to the interaction between angiotensin-converting enzyme 2 (ACE2) and blood group antigens. However, the relationship between blood type to clinical outcome in critically ill patients and the mechanism of action is still unclear. The current study aimed to examine the correlation between blood type distribution and SARS-CoV-2 infection, progression, and prognosis in patients with COVID-19 and the potential mediating role of ACE2. With 234 patients from 5 medical centers and two established cohorts, 137 for the mild cohort and 97 for the critically ill cohort, we found that the blood type A population was more sensitive to SARS-CoV-2, while the blood type distribution was not relevant to acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), and mortality in COVID-19 patients. Further study showed that the serum ACE2 protein level of healthy people with type A was significantly higher than that of other blood groups, and type O was the lowest. The experimental results of spike protein binding to red blood cells also showed that the binding rate of people with type A was the highest, and that of people with type O was the lowest. Our finding indicated that blood type A may be the biological marker for susceptibility to SARS-CoV-2 infection and may be associated with potential mediating of ACE2, but irrelevant to the clinical outcomes including ARDS, AKI, and death. These findings can provide new ideas for clinical diagnosis, treatment, and prevention of COVID-19.

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

Effect of olmesartan and amlodipine on serum angiotensin-(1–7) levels and kidney and vascular function in patients with type 2 diabetes and hypertension

BackgroundRecent studies suggest that angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) [Ang-(1–7)] might have beneficial effects on the cardiovascular system. We investigated the effects of olmesartan on the changes in serum ACE2 and Ang-(1–7) levels as well as kidney and vascular function in patients with type 2 diabetes and hypertension.MethodsThis was a prospective, randomized, active comparator-controlled trial. Eighty participants with type 2 diabetes and hypertension were randomized to receive 20 mg of olmesartan (N = 40) or 5 mg of amlodipine (N = 40) once daily. The primary endpoint was changes of serum Ang-(1–7) from baseline to week 24.ResultsBoth olmesartan and amlodipine treatment for 24 weeks decreased systolic and diastolic blood pressures significantly by > 18 mmHg and > 8 mmHg, respectively. Serum Ang-(1–7) levels were more significantly increased by olmesartan treatment (25.8 ± 34.5 pg/mL → 46.2 ± 59.4 pg/mL) than by amlodipine treatment (29.2 ± 38.9 pg/mL → 31.7 ± 26.0 pg/mL), resulting in significant between-group differences (P = 0.01). Serum ACE2 levels showed a similar pattern (6.31 ± 0.42 ng/mL → 6.74 ± 0.39 ng/mL by olmesartan treatment vs. 6.43 ± 0.23 ng/mL → 6.61 ± 0.42 ng/mL by amlodipine treatment; P < 0.05). The reduction in albuminuria was significantly associated with the increases in ACE2 and Ang-(1–7) levels (r = − 0.252 and r = − 0.299, respectively). The change in Ang-(1–7) levels was positively associated with improved microvascular function (r = 0.241, P < 0.05). Multivariate regression analyses showed that increases in serum Ang-(1–7) levels were an independent predictor of a reduction in albuminuria.ConclusionsThese findings suggest that the beneficial effects of olmesartan on albuminuria may be mediated by increased ACE2 and Ang-(1–7) levels. These novel biomarkers may be therapeutic targets for the prevention and treatment of diabetic kidney disease.Trial registration: ClinicalTrials.gov NCT05189015.

Repurposing UDCA, an FXR Inhibitor, to Prevent SARS-Cov-2 Infection

Brevini T, Maes M, Webb GJ, et al. FXR Inhibition May Protect From SARS-CoV-2 Infection by Reducing ACE2. Nature 2022 Dec 5. https://doi.org/10.1038/s41586-022-05594-0. Viruses need to access the host’s machinery to replicate and propagate, and do so by binding to their respective receptors on host cells. Angiotensin-converting enzyme 2 (ACE2) was identified early in the pandemic as the entryway for the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Since then, scientists have been exploring ways to prevent SARS-Cov-2 infection by targeting ACE2. In a study published in Nature, Brevini et al identified farnesoid X receptor (FXR) as a regulator of ACE2 expression. FXR is a ubiquitous bile acid sensing protein. Upon its activation by chenodeoxycholic acid, ACE2 increased in biliary, airway, and intestinal organoids. FXR directly bound the ACE2 promoter and activated its transcription. Furthermore, suppressing FXR signaling with ursodeoxycholic acid (UDCA) or Z-guggulsterone–reduced ACE2 expression. To test its relevance to coronavirus disease 2019 (COVID-19) in vitro, organoids were stimulated with chenodeoxycholic acid and infected with SARS-Cov-2 in the presence or absence of UDCA or Z-guggulsterone. Reduced viral infection was measured when drugs were present. In vivo, UDCA treatment decreased ACE2 expression in tissues of mice and hamsters. Furthermore, the Syrian Hamster model showed replication and transmission of SARS-Cov-2 in all untreated animals, whereas only 3 of 9 UDCA-treated animals were infected, and they presented a milder disease course. Interestingly, the authors took several approaches to validate their findings in the human context. They first used donated organs that were unfit for transplantation. They performed ex situ normothermic perfusion on a pair of lungs, whereby 1 lung received UDCA in the perfusate and the other served as a matched control. UDCA treatment decreased ACE2 expression in lung cells and ACE2 activity in the perfusate. Importantly, UDCA treatment decreased infection when lungs were exposed to SARS-Cov-2. Similar observations were seen with liver grafts. Additionally, they determined that UDCA reduced ACE2 expression in the nasal epithelium of healthy volunteers who received UDCA. They also retrospectively found an inverse correlation between UDCA and serum ACE2 levels in a serum proteomics dataset of a patient cohort. Finally, the authors interrogated 2 COVID-19 databases, one composed of patients with chronic liver disease and the other of vaccinated liver transplant recipients. In both scenarios, patients receiving UDCA had better COVID-19 outcomes compared with matched controls. Brevini et al were clever in their approaches. They repurposed donated organs found unfit for transplantation, giving them a new benefit for preclinical drug testing with potentially better predictive power. More important, they repurposed an approved and off-patent drug, UDCA, to prevent SARS-Cov-2 infection, a novel approach against viral infection that is directed toward the host rather than the virus. Because ACE2 is a receptor for many viruses, UDCA may have broader use and is less susceptible to immune escape by viruses. Although the experimental data shown were strong, it remains to be seen how UDCA performs in clinical trials involving larger and controlled cohorts of patients. Nonetheless, the repurposing of a cost-effective and readily available drug to prevent viral infection alongside vaccination is exciting and promising.

Measuring of Specific Bone Alkaline phosphatase ( BAP ) Bone Remodeling biomarker for Post-COVID Iraqi Patient

Background: There are several diseases in the body following recovery from COVID-19 infection because this virus operates on human genes in various types of peripheral tissue in the human body. It penetrates host cells via Angiotensin-converting enzyme-2 receptors and may have effects on bone remodeling, leading to osteopenia or osteoporosis, which are characterized by low bone mineral density, resulting in diminished bone strength. Bone Alkaline Phpsphatase is an enzyme released into the bloodstream as a soluble homodimer after being cleaved by a phospholipase and can be utilized as a biomarker of bone development. Objective: This research was designed to investigate the alteration of bone homeostasis balance in Iraqi post-COVID-19 infection patients. Cases and Methods: This is a case control study. The study has received approval from the ethical committee at the Faculty of Medicine, Baghdad University, established on November 20, 2021–March 2, 2022. A hundred and thirty individuals were enrolled in this study. The subjects were divided into two groups; the first group (80) post-COVID-19 infection patients and the second group (50) non-COVID-19 individuals. Also, measuring markers like serum Angiotensin-converting enzyme-2 and Bone Alkaline Phosphatase by using the ELISA technique. The bone mineral density was measured by a DEXA scan. Results:This study found that there is an effect of coronavirus infection on the bone strength measured by the mean ± SD Bone Alkaline Phosphatase level, which was found to be highly significant in the serum of post-COVID-19 patients when compared with non-COVID-19 individuals (P-value = 0.001), but the mean ± SD of Angiotensin-converting enzyme-2 level was statistically non-significant between the two groups (P-value = 0.13). who had recovered from a coronavirus infection for 3 months or more. Also, the bone mineral density of Post COVID-19 patients that was measured by DEXA scan had a highly significant T-score% when compared between the two groups. Conclusions:This research found that COVID-19 has an impact on the bone remodeling process, leading to osteopenia or osteoporosis, which may be identified by checking the blood levels of the bone biomarker BAP and the bone mineral density (by DEXA scan) at least three months following coronavirus recovery. This investigation also discovered that some of the individuals had osteopenia rather than osteoporosis.

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.

Serum levels of angiotensin-converting enzyme 2 in children with Kawasaki disease

Kawasaki disease (KD) has replaced rheumatic fever as the main cause of acquired heart disease in Japanese, American, and Chinese children. Polymorphisms in angiotensin-converting enzyme may be associated with susceptibility to KD, but the association of angiotensin-converting enzyme 2 (ACE2) with vascular endothelial injury in KD and the possibility for prognosis of vascular injury in KD by evaluating changes in serum ACE2 have not yet been assessed. Thus, this study aimed to investigate ACE2 levels in patients with KD to further explore the relationship between ACE2 and vascular injury in KD. Blood samples were collected from 49 children with KD before intravenous immunoglobulin treatment and 28 healthy children in the same period as the control group. Clinical data were collected from the patients and serum ACE2 levels of all participants were measured using an enzyme-linked immunosorbent assay. Serum ACE2 levels were significantly higher in the KD group than in the control group, and were negatively correlated with platelet levels in patients with KD. Serum ACE2 levels are related to the pathogenesis of KD and may be used as a potential serum marker for KD diagnosis.

Serum angiotensin-converting enzyme 2 as a potential biomarker for SARS-CoV-2 infection and vaccine efficacy.

Various species of the SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE2), are present in serum, which may result from virus entry and subsequent proteolytic processing of the membrane receptor. We have recently demonstrated changes of particular ACE2 species in virus infected humans, either cleaved fragments or circulating full-length species. Here, we further explore the potential of serum ACE2 as a biomarker to test SARS-CoV-2 infection and vaccine efficacy in virus susceptible transgenic K18-hACE2 mice expressing human ACE2. First, in serum samples derived from K18-hACE2 mice challenged with a lethal dose of SARS-CoV-2, we observed an increase in the levels of cleaved ACE2 fragment at day 2 post-challenge, which may represent the subsequent proteolytic processing through virus entry. These elevated levels were maintained until the death of the animals at day 6 post-challenge. The circulating full-length ACE2 form displayed a sizable peak at day 4, which declined at day 6 post-challenge. Noticeably, immunization with two doses of the MVA-CoV2-S vaccine candidate prevented ACE2 cleaved changes in serum of animals challenged with a lethal dose of SARS-CoV-2. The efficacy of the MVA-CoV2-S was extended to vaccinated mice after virus re-challenge. These findings highlight that ACE2 could be a potential serum biomarker for disease progression and vaccination against SARS-CoV-2.

Intrinsic Exercise Capacity Affects Glycine and Angiotensin-Converting Enzyme 2 (ACE2) Levels in Sedentary and Exercise Trained Rats

Angiotensin-converting enzyme 2 (ACE2) has been identified as the cellular entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High ACE2 tissue expression and low glycine levels were suggested to increase susceptibility for SARS-CoV-2 infection and increasing circulating ACE2 has been proposed as one possible strategy to combat COVID-19. In humans, aerobic physical exercise induces an increase in plasma ACE2 in some individuals. However, it is not clear whether glycine and ACE2 levels depend on intrinsic exercise capacity or on exercise training. We used rats selectively bred for high intrinsic exercise capacity (HCR) or low exercise capacity (LCR) and tested the influence of this genetic predetermination and/or aerobic exercise on metabolites, ACE2 tissue expression and circulating ACE 2. ACE2 expression was measured in different tissues in the sedentary animals and again after 4 weeks of high-intensity aerobic exercise in both LCRs and HCRs. Sedentary HCRs exhibited significantly higher circulating ACE2 concentrations compared to LCRs, but a lower expression of ACE2 in all investigated tissues except for adipose tissue. Body weight was negatively correlated with serum ACE2 and positively correlated with ACE2 expression in the heart. Aerobic exercise caused a significant decrease in ACE2 expression in the lung, heart, muscle, and kidney both in LCRs and HCRs. Our results suggest that ACE2 expression, circulating ACE2 and glycine serum concentration are related to aerobic intrinsic exercise capacity and can be influenced with exercise. These results may support the hypothesis that physically fit individuals have a lower susceptibility for COVID-19 infection.

Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson´s disease

The role of autoimmunity in neurodegeneration has been increasingly suggested. The renin-angiotensin system (RAS) autoantibodies play a major role in several peripheral inflammatory processes. Dysregulation of brain RAS has been involved in neuroinflammation and neurodegeneration. We aimed to know whether angiotensin type-1 receptor (AT1) autoantibodies (AT1 agonists) and angiotensin-converting enzyme 2 (ACE2) autoantibodies (ACE2 antagonists) may be involved in Parkinson’s disease (PD) progression and constitute a new therapeutical target. Both AT1 and ACE2 serum autoantibodies were higher in a group of 117 PD patients than in a group of 106 controls. Serum AT1 autoantibodies correlated with several cytokines, particularly Tumor Necrosis Factor Ligand Superfamily Member 14 (TNFSF14, LIGHT), and 27-hydroxycholesterol levels. Serum ACE2 autoantibodies correlated with AT1 autoantibodies. Both autoantibodies were found in cerebrospinal fluid (CSF) of four PD patients with CSF samples. Consistent with the observations in patients, experimental dopaminergic degeneration, induced by 6-hydroxydopamine, increased levels of autoantibodies in serum and CSF in rats, as well as LIGHT levels and transglutaminase activity in rat substantia nigra. In cultures, administration of AT1 autoantibodies enhanced dopaminergic neuron degeneration and increased levels of neuroinflammation markers, which was inhibited by the AT1 antagonist candesartan. The results suggest dysregulation of RAS autoantibodies as a new mechanism that can contribute to PD progression. Therapeutical strategies blocking the production, or the effects of these autoantibodies may be useful for PD treatment, and the results further support repurposing AT1 blockers (ARBs) as treatment against PD progression.

The Predictive Value of Serum ACE2 and TMPRSS2 Concentrations in Patients with COVID-19-A Prospective Pilot Study.

One of the major challenges for healthcare systems during the Coronavirus-2019 (COVID-19) pandemic was the inability to successfully predict which patients would require mechanical ventilation (MV). Angiotensin-Converting Enzyme 2 (ACE2) and TransMembrane Protease Serine S1 member 2 (TMPRSS2) are enzymes that play crucial roles in SARS-CoV-2 entry into human host cells. However, their predictive value as biomarkers for risk stratification for respiratory deterioration requiring MV has not yet been evaluated. We aimed to evaluate whether serum ACE2 and TMPRSS2 levels are associated with adverse outcomes in COVID-19, and specifically the need for MV. COVID-19 patients admitted to an Israeli tertiary medical center between March--November 2020, were included. Serum samples were obtained shortly after admission (day 0) and again following one week of admission (day 7). ACE2 and TMPRSS2 concentrations were measured with ELISA. Of 72 patients included, 30 (41.6%) ultimately required MV. Serum ACE2 concentrations >7.8 ng/mL at admission were significantly associated with the need for MV (p = 0.036), inotropic support, and renal replacement therapy. In multivariate logistic regression analysis, elevated ACE2 at admission was associated with the need for MV (OR = 7.49; p = 0.014). To conclude, elevated serum ACE2 concentration early in COVID-19 illness correlates with respiratory failure necessitating mechanical ventilation. We suggest that measuring serum ACE2 at admission may be useful for predicting the risk of severe disease.

High serum angiotensin-converting enzyme 2 activity as a biomarker of frailty in nursing home residents.

Angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) are two of the main components of the renin-angiotensin system (RAS). Imbalanced RAS showing lower ACE2 has been associated with increased cardiovascular risk, muscular pathologies, sarcopenia, frailty, other age-related pathologies and a poorer health status. However, its role in aging remains unclear. Thus, the aim of this work was to analyze the serum enzymatic activity of ACE and ACE2, the ACE/ACE2 ratio and its association with anthropometric parameters, blood pressure, physical function, dependence and frailty in older people living in nursing homes. This study is a secondary analysis of baseline data from two randomized clinical trials in a population of 228 older individuals living in nursing homes (Spain). Serum ACE and ACE2 enzymatic activities were measured by fluorimetry. Variables linked to cardiovascular risk, physical function, dependence and frailty were measured using validated tests, indexes and scales. Association between ACE, ACE2 serum activities, the ACE/ACE2 ratio and the rest of the quantitative variables were assessed by Pearson's correlations and by partial correlations controlled by age and sex. The association between serum ACE and ACE2 activities, the ACE/ACE2 ratio and frailty scores was analyzed by generalized linear models with and without controlling for sex and age. Differences in enzymatic activities between sexes and between frail and non-frail individuals were analyzed using Student's t-test and general linear models to control analysis by age and sex. We found that higher serum ACE2 activity was associated with a higher body mass index, worse physical function, greater dependence and increased frailty. This association is consistent with the elevation of circulating ACE2 in certain pathological conditions and in line with RAS deregulation in muscular dystrophies. Serum ACE2 activity, in combination with other molecules, could be proposed as a biomarker of poor physical function, higher dependence and frailty.

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.

Serum HMGB1, DKK1, and ACE2 as a Function of Lung Injuries in COVID-19 Patients

There is a need for a biomarker for lung injury in COVID-19 patients. In the present study, an attempt was carried out to examine the role of Dickkopf-related protein 1 (DKK1), High-mobility group box 1 protein (HMGB1), angiotensin-converting enzyme 2 (ACE2) as a function for the lung abnormalities in CT-scan (LACTS). To perform the goals, DKK1, HMGB1, and ACE2 were measured in patients and controls using the ELISA technique. In contrast, other parameters were measured spectrophotometrically. The results showed decreased SpO2 and albumin and an increase in the serum biochemical parameters (glucose, urea, creatinine, D-dimer, ACE2, DKK1, and HMGB1) in COVID-19 patients compared with the control group. In COVID-19 patients, the percentages of the lung abnormalities in CT-scan% are 40.67±11.84. The results showed that those patients with LACTS patients are slightly older and have lower SpO2 than the patients without the LACTS group. ACE2 shows a significant correlation with SpO2 (ρ = 0.336, p&lt;0.01) and a negative correlation with albumin (ρ = -0.197, p&lt;0.05). Other parameters showed no significant correlation with the measured biomarkers. In conclusion, COVID-19 patients have higher ACE, DKK1, and HMGB1 indicating the involvement of the pathways of these biomarkers in the disease progression including lung injury.

Is there any relationship between serum zinc levels and angiotensin-converting enzyme 2 gene expression in patients with coronavirus disease 2019?

BackgroundThe level of angiotensin-converting enzyme 2 (ACE2) expression in different tissues is essential in the sensitivity, symptoms and consequences of COVID-19 infection. It seems that zinc is involved in the structure of the ACE2 enzyme has been identified; nonetheless, the relationship between ACE2 expression and zinc serum levels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients is still unclear. This study aimed to evaluate the expression of ACE2 in peripheral blood-derived immune cells of COVID-19 patients and its relationship with serum zinc levels. MethodsThirty healthy subjects and thirty patients with COVID-19 were enrolled in this study. The COVID-19 infection was confirmed by positive real-time polymerase chain reaction (RT-PCR) and radiological data. Peripheral blood samples were taken from healthy subjects and COVID-19 patients. Whole blood samples were also used to measure ACE2 gene expression by RT-PCR technique. The correlation matrix evaluated the relationship between ACE2 expression, serum zinc levels, and other related variables. ResultsThe outcomes showed no considerable alteration in serum zinc levels between patients and the control group. Likewise, the ACE2 gene expression results showed a significant decrease in this receptor's expression in COVID-19 patients compared with the healthy subjects. A significant positive correlation was observed between serum zinc level and ACE2 gene expression in patients with COVID-19. ConclusionThe immune system seems to reduce the mRNA expression of the ACE2 in the peripheral blood leukocytes following SARS-CoV-2 infection. Moreover, zinc deficiency can make patients more susceptible to SARS-CoV-2 infection.