Plasma Angiotensin-converting Enzyme 2 Research Articles

Haematological Profile and ACE2 Levels of COVID-19 Patients in a Metropolis in Ghana

Background: Several studies have linked coronavirus disease 2019 (COVID-19) risk to age and ABO blood groups. Variations in plasma angiotensin-converting enzyme 2 (ACE2) levels and blood counts have been reported, suggesting an association between disease severity and low lymphocyte levels. Aim: this study aimed to understand how these factors relate to COVID-19 in Ghanaian patients, considering geographical and demographic differences. Methods: Participants were recruited from six hospitals in Kumasi, Ghana, between June 2020 and July 2021. Nasopharyngeal swabs were taken to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and blood samples were collected for complete blood count testing, ABO/Rhesus typing, and assessment of plasma ACE2 levels. Demographic and COVID-19 severity data were gathered, and IBM SPSS version 25.0 was used for analysis. Results: Overall, 515 patients were enrolled, out of which 55.9% (n = 288/515) were males and 50.3% (n = 259/515) tested positive for SARS-CoV-2. The median age was 37 years (IQR = 26–53). Age was significantly associated with SARS-CoV-2 infection (p = 0.002). The severe COVID-19 group was the oldest (70 years, IQR = 35–80) and presented with anaemia (haemoglobin, g/dL: 9.55, IQR = 7.85–11.93), leukocytosis (WBC × 103/μL: 15.87, IQR = 6.68–19.80), neutrophilia (NEUT × 106/μL: 14.69, IQR = 5.70–18.96) and lymphocytopenia (LYMPH × 106/μL: 0.47, IQR = 0.22–0.66). No association was found between SARS-CoV-2 positivity and ABO (p = 0.711) or Rh (p = 0.805) blood groups; no association was also found between plasma ACE2 levels and SARS-CoV-2 status (p = 0.079). However, among COVID-19 participants, plasma ACE2 levels were significantly reduced in the moderate illness group (40.68 ng/mL, IQR = 34.09–48.10) compared with the asymptomatic group (50.61 ng/mL, IQR = 43.90–58.61, p = 0.015). Conclusions: While there may be no real association between the ABO blood group, as well as plasma ACE2 levels, and SARS-CoV-2 infection in Ghanaian patients, older individuals are at a higher risk of severe disease. Anaemia, and leukocytosis with lymphocytopenia may be indicators of poor disease progression.

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.

Ectodomain shedding of proteins important for SARS-CoV-2 pathogenesis in plasma of tobacco cigarette smokers compared to electronic cigarette vapers: a cross-sectional study.

The impact of tobacco cigarette (TCIG) smoking and electronic cigarette (ECIG) vaping on the risk of development of severe COVID-19 is controversial. The present study investigated levels of proteins important for SARS-CoV-2 pathogenesis present in plasma because of ectodomain shedding in smokers, ECIG vapers, and non-smokers (NSs). Protein levels of soluble angiotensin-converting enzyme 2 (ACE2), angiotensin (Ang) II (the ligand of ACE2), Ang 1-7 (the main peptide generated from Ang II by ACE2 activity), furin (a protease that increases the affinity of the SARS-CoV-2 spike protein for ACE2), and products of ADAM17 shedding activity that predict morbidity in COVID-19 (IL-6/IL-6R alpha (IL-6/IL-6Rα) complex, soluble CD163 (sCD163), L-selectin) were determined in plasma from 45 NSs, 30 ECIG vapers, and 29 TCIG smokers using ELISA. Baseline characteristics of study participants did not differ among groups. TCIG smokers had increased sCD163, L-selectin compared to NSs and ECIG vapers (p < 0.001 for all comparisons). ECIG vapers had higher plasma furin compared to both NSs (p < 0.001) and TCIG smokers (p < 0.05). ECIG vaping and TCIG smoking did not impact plasma ACE2, Ang 1-7, Ang II, and IL-6 levels compared to NSs (p > 0.1 for all comparisons). Further studies are needed to determine if increased furin activity and ADAM17 shedding activity that is associated with increased plasma levels of sCD163 and L-selectin in healthy young TCIG smokers may contribute to the future development of severe COVID-19 and cardiovascular complications of post-acute COVID-19 syndrome.

PS-C24-8: PLASMA ANGIOTENSIN CONVERTING ENZYME 2 ACTIVITY IN HOSPITALISED PATIENTS WITH ACUTE HEART FAILURE CLASSIFIED BY LEFT VENTRICULAR EJECTION FRACTION

Objective: Angiotensin-converting enzyme 2 (ACE2) is present on endothelial cells with a role to degrade angiotensin II. In this study, we investigate plasma ACE2 levels in patients admitted with acute decompensated heart failure (ADHF) and determine if levels differ according to ejection fraction (EF). Design and Method: We prospectively recruited 9 controls and 117 ADHF inpatients, determined EF using echocardiography, measured plasma ACE2 activity using an in-house assay and NT-proBNP levels using a commercially available assay. Patients were classified according to 2021 European Guidelines as HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) or preserved EF (HFpEF). Results: In addition to NT-proBNP level, median plasma ACE2 activity was increased in ADHF patients (n = 117) compared to controls (1.33 [0.02, 4.02] vs 15.36 [9.02, 27.9] pmol/mL/min, p &lt; 0.0001). In ADHF, plasma ACE2 activity was negatively associated with EF (r = -0.43, p &lt; 0.0001). Overall, 58% of patients had HFrEF, 10% had HFmrEF and 32% had HFpEF. Patients with HFrEF had a higher median plasma ACE2 activity compared to those with HFpEF (18.3 [12.3, 30.0] vs 11.4 [4.8, 17.9] pmol/mL/min, p = 0.001) and higher NT-proBNP levels (p = 0.001). There was no difference in plasma ACE2 activity between patients with HFmrEF and HFpEF or HFmrEF and HFrEF. Conclusions: Plasma ACE2 activity is elevated in patients hospitalised with ADHF and is significantly higher in HFrEF compared to other types of HF. Further studies are needed to determine if measurement of plasma ACE2 can assist in better definition /classification of the patient phenotype to facilitate improved treatment.

S-28-5: CIRCULATING ANGIOTENSIN CONVERTING ENZYME 2 ACTIVITY AS A CARDIOVASCULAR RISK MARKER IN A YOUNG HEALTHY POPULATION: THE AFRICAN-PREDICT STUDY

Objective: Cardiovascular disease (CVD) remains the major contributor to premature death globally, with black populations presenting with a disproportionate burden of CVD and early target organ damage. Renin angiotensin system dysregulation is a key factor involved in hypertension development and organ damage in black populations. Angiotensin converting enzyme 2 (ACE2) counteracts the deleterious effects of angiotensin II, and increased circulating ACE2 predicts cardiovascular events and mortality in the general population, and in patients with CVD. However, the role of ACE2 activity as a cardiovascular risk marker in young healthy individuals remains largely unclear. We explored ethnic and sex differences in ACE2 activity and associations between blood pressure (BP), left ventricular mass index (LVMi) and ACE2 activity in young healthy black and white adults. Design and method: We included 1134 black (men, N = 280; women, N = 285) and white (men, N = 277; women, N = 292) participants aged 20–30 years. The participants were normotensive at screening (BP≦140/90 mmHg) with no known CVD. Ambulatory systolic and diastolic BP were recorded and LVMi (m2.7) was obtained from echocardiography and plasma ACE2 activity measured using a validated assay. Results: Overall, mean plasma ACE2 activity was higher in black [1.33 pmol/min/ml (0.02; 19.6)] than in white [0.73 pmol/min/ml (0.02; 12.5)] participants, and higher in men [3.63 pmol/min/ml (0.02; 20.5)] than in women [0.28 pmol/min/ml (0.02; 9.87)] (both P &lt; 0.001). When comparing ethnic groups according to sex, ACE2 activity was higher in black men and women than in white men and women (both P ≦ 0.012). After adjustments for covariates (ethnicity, sex, age, body mass index, socioeconomic status, physical activity, glucose, low density lipoprotein cholesterol, C-reactive protein, alcohol intake and smoking), 24-hour systolic BP was positively associated with ACE2 activity in the total group (R2 = 0.43; β=0.07; P = 0.019) and black men (R2 = 0.19; β=0.18; P = 0.007). There were no independent associations of diastolic BP and LVMi with ACE2 activity in any of the groups. Conclusions: 24-hour systolic BP was independently and positively associated with ACE2 activity in the total group. When stratifying the group according to ethnicity and sex, a similar association was evident in black men, a group previously identified to be at high cardiovascular risk. The observed ethnic and sex differences in ACE2 activity and associations with BP suggest that ACE2 may be a useful biomarker in cardiovascular risk profiling in young populations.

Effects of Two Soluble ACE2-Fc Variants on Blood Pressure and Albuminuria in Hypertensive Mice: Research Letter.

Angiotensin-converting enzyme 2 (ACE2) hydrolyzes angiotensin (Ang) II to Ang-(1-7), promoting vasodilatation, and inhibiting oxidative stress and inflammation. Plasma membrane ACE2 is the receptor for all known SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) viral variants. In COVID-19 infection, soluble ACE2 variants may act as decoys to bind and neutralize the coronavirus, reducing its tissue infectivity. Furthermore, soluble ACE2 variants have been proposed as potential therapeutics for kidney disease and hypertensive disorders. Soluble ACE2 variants conjugated to human Fc domains and selected for high-potency viral SARS-CoV-2 neutralization were prepared and evaluated for ACE2 activity in vitro. Lead candidates were then tested for systemic ACE2 activity, stability, and effects on blood pressure and albuminuria in mice with Ang II-induced hypertension. ACE2 activity of 10 soluble ACE2 variants was first assessed in cell-free conditions using a fluorogenic substrate, or by Ang II hydrolysis to Ang-(1-7). Hypertension was induced in male or female mice by implantation of osmotic minipumps containing Ang II. Two lead ACE2 variants were injected intravenously (i.v.) into hypertensive mice, followed by measurements of blood pressure (tail-cuff plethysmography), albuminuria, and tissue ACE2 activity and protein (immunoblots). Soluble ACE2-Fc variants demonstrated significant ACE2 enzymatic activity, with kinetics comparable with human recombinant ACE2. In hypertensive mice, single dose i.v. injection of ACE2-Fc variant K (10 mg/kg) significantly decreased systolic blood pressure at 24 hours, with partial lowering sustained to 48 hours, and tendency to reduce albuminuria at 72 hours. By contrast, ACE2-Fc variant I had no effect on blood pressure or albuminuria in hypertensive mice; ACE2-Fc variant K was detected by immunoblotting in plasma, kidney, heart, lung, liver, and spleen lysates 72 hours after injection, associated with significantly increased ACE2 activity in all tissues except kidney and spleen. Angiotensin-converting enzyme 2-Fc variant I had no effect on plasma ACE2 activity. Soluble ACE2-Fc variant K reduces blood pressure and tends to lower albuminuria in hypertensive mice. Furthermore, soluble ACE2-Fc variant K has prolonged tissue retention, associated with increased tissue ACE2 activity. The results support further studies directed at the therapeutic potential of soluble ACE2-Fc variant K for cardiovascular and kidney protection.

Angiotensin-converting enzyme 2 in human plasma and lung tissue

PurposeWe investigated plasma angiotensin-converting enzyme 2 (ACE2) concentration in a population sample and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue in patients who underwent lung surgery.Materials and methodsThe study participants were recruited from a residential area in the suburb of Shanghai for the plasma ACE2 concentration study (n = 503) and the lung tissue samples were randomly selected from the storage in Ruijin Hospital (80 men and 78 age-matched women).ResultsIn analyses adjusted for covariables, men had a significantly higher plasma ACE2 concentration (1.21 vs. 0.98 ng/mL, p = 0.027) and the mean intensity of ACE2 in the lung tissue (55.1 vs. 53.9 a.u., p = 0.037) than women. With age increasing, plasma ACE2 concentration decreased (p = 0.001), while the mean intensity of ACE2 in the lung tissue tended to increase (p = 0.087). Plasma ACE2 concentration was higher in hypertension than normotension, especially treated hypertension (1.23 vs. 0.98 ng/mL, p = 0.029 vs. normotension), with no significant difference between users of RAS inhibitors and other classes of antihypertensive drugs (p = 0.64). There was no significance of the mean intensity of ACE2 in the lung tissue between patients taking and those not taking RAS inhibitors (p = 0.14). Neither plasma ACE2 concentration nor the mean intensity of ACE2 in the lung tissue differed between normoglycemia and diabetes (p ≥ 0.20).ConclusionACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics of patients.Plain language summary What is the context? • The primary physiological function of ACE2 is the degradation of angiotensin I and II to angiotensin 1-9 and 1-7, respectively. • ACE2 was found to behave as a mediator of the severe acute respiratory syndrome coronavirus (SARS) infection. • There is little research on ACE2 in humans, especially in the lung tissue. • In the present report, we investigated plasma ACE2 concentration and the ACE2 expression quantitated with the diaminobenzidine mean intensity in the lung tissue respectively in two study populations. What is new? • Our study investigated both circulating and tissue ACE2 in human subjects. The main findings were: • In men as well as women, plasma ACE2 concentration was higher in younger than older participants, whereas the mean intensity of ACE2 in the lung tissue increase with age increasing. • Compared with normotension, hypertensive patients had higher plasma ACE2 concentration but similar mean intensity of ACE2 in the lung tissue. • Neither plasma ACE2 concentration nor lung tissue ACE2 expression significantly differed between users of RAS inhibitors and other classes of antihypertensive drugs. What is the impact? • ACE2 in the plasma and lung tissue showed divergent changes according to several major characteristics, such as sex, age, and treated and untreated hypertension. • A major implication is that plasma ACE2 concentration might not be an appropriate surrogate for the ACE2 expression in the lung tissue, and hence not a good predictor of SARS-COV-2 infection or fatality.

Angiotensin-converting Enzyme-2 (ACE2) Expression in Pediatric Liver Disease.

The membrane protein angiotensin-converting enzyme-2 (ACE2) has gained notoriety as the receptor for severe acute respiratory syndrome coronavirus 2. Prior evidence has shown ACE2 is expressed within the liver but its function has not been fully discerned. Here, we utilized novel methodology to assess ACE2 expression in pediatric immune-mediated liver disease to better understand its presence in liver diseases and its role during infections such as COVID-19. We stained liver tissue with ACE2-specific immunofluorescent antibodies, analyzed via confocal microscopy. Computational deep learning-based segmentation models identified nuclei and cells, allowing the quantification of mean cellular and cytosolic immunofluorescent. Spatial transcriptomics provided high-throughput gene expression analysis in tissue to determine cellular composition for ACE2 expression. ACE2 plasma expression was quantified via enzyme-linked immunosorbent assay. High ACE2 expression was seen at the apical surface of cholangiocytes, with lower expression within hepatocyte cytosol and nonparenchymal cells ( P <0.001). Children with liver disease had higher ACE2 hepatic expression than pediatric control tissue ( P <0.001). Adult control tissue had higher expression than pediatric control ( P <0.001). Plasma ACE2 was not found to be statistically different between samples. Spatial transcriptomics identified cell composition of ACE2-expressing spots containing antibody-secreting cells. Our results show ACE2 expression throughout the liver, with strongest localization to cholangiocyte membranes. Machine learning can be used to rapidly identify hepatic cellular components for histologic analysis. ACE2 expression in the liver may be increased in pediatric liver disease. Future work is needed to better understand the role of ACE2 in chronic disease and acute infections.

Plasma Angiotensin Converting Enzyme 2 (ACE2) Activity in Healthy Controls and Patients with Cardiovascular Risk Factors and/or Disease.

Angiotensin converting enzyme 2 (ACE2) is an endogenous negative regulator of the renin-angiotensin system, a key factor in the development of cardiovascular disease (CVD). ACE2 is also used by SARS-CoV-2 for host cell entry. Given that COVID-19 is associated with hypercoagulability, it is timely to explore the potential relationship between plasma ACE2 activity and the coagulation profile. In this cross-sectional study, ACE2 activity and global coagulation assays (GCA) including thromboelastography, thrombin, and fibrin generation were measured in adult healthy controls (n = 123; mean age 41 ± 17 years; 35% male) and in patients with cardiovascular risk factors and/or disease (n = 258; mean age 65 ± 14 years; 55% male). ACE2 activity was significantly lower in controls compared to patients with cardiovascular risk factors and/or disease (median 0.10 (0.02, 3.33) vs. 5.99 (1.95, 10.37) pmol/mL/min, p < 0.001). Of the healthy controls, 48% had undetectable ACE2 activity. Controls with detectable ACE2 had lower maximum amplitude (p < 0.001). In patients with cardiovascular risk factors and/or disease, those in the 3rd tertile were older and male (p = 0.002), with a higher Framingham grade and increased number of cardiovascular risk factors (p < 0.001). In conclusion, plasma ACE2 activity is undetectable to very low in young healthy controls with minimal clinically relevant associations to GCA. Patients with cardiovascular risk factors and/or disease have increased plasma ACE2 activity, suggesting that it may be an important biomarker of endothelial dysfunction and atherosclerosis.

Early shedding of membrane-bounded ACE2 could be an indicator for disease severity in SARS-CoV-2

SARS-CoV-2 uses membrane bound Angiotensin-Converting Enzyme 2 (ACE2) as a key host receptor for its entry. However, inconsistent results are available in terms of shedding of membrane ACE2 and circulating levels of soluble ACE2 during SARS-CoV-2. To ascertain soluble ACE2 as an effective biomarker for the prediction of COVID-19 outcome, in the present study, we investigated the levels of plasma ACE2 during the early phase of infection in COVID-19 patients. The study involved a total of 42 COVID-19 patients along with 10 healthy controls. Plasma levels of ACE2 was determined using ELISA at the time of admission and on day 7 post admission. The association of sACE2 with D-dimer a marker for hyper-coagulation was performed using a dependence test. Compared to healthy controls, SARS-CoV-2 cases has shown a huge increase in the sACE2 at the time of admission. During the course of infection, we found a significant increase (P ≤ 0.001) in sACE2 in severe cases compared to moderate. There was a strong increase in sACE2 in cases with hypertension and diabetes mellitus. Interestingly, a strong positive correlation (P ≤ 0.001) was obtained between sACE2 and D-dimer. Thus, an excessive shedding of ACE2 during the early phase is a common phenomenon in severe form of the SARS-CoV-2. Along with D-dimer, the sACE2 levels could serve as a clinical biomarker for the prediction of disease outcome. However further studies are needed to ascertain its role in host-virus interplay.

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.

IRW (Isoleucine-Arginine-Tryptophan) Improves Glucose Tolerance in High Fat Diet Fed C57BL/6 Mice via Activation of Insulin Signaling and AMPK Pathways in Skeletal Muscle.

IRW (Isoleucine–Arginine–Tryptophan), has antihypertensive and anti-inflammatory properties in cells and animal models and prevents angiotensin-II- and tumor necrosis factor (TNF)-α-induced insulin resistance (IR) in vitro. We investigated the effects of IRW on body composition, glucose homeostasis and insulin sensitivity in a high-fat diet (HFD) induced insulin resistant (IR) model. C57BL/6 mice were fed HFD for 6 weeks, after which IRW was incorporated into the diet (45 or 15 mg/kg body weight (BW)) until week 14. IRW45 (at a dose of 45 mg/kg BW) reduced BW (p = 0.0327), fat mass gain (p = 0.0085), and preserved lean mass of HFD mice (p = 0.0065), concomitant with enhanced glucose tolerance and reduced fasting glucose (p < 0.001). In skeletal muscle, IRW45 increased insulin-stimulated protein kinase B (AKT) phosphorylation (p = 0.0132) and glucose transporter 4 (GLUT4) translocation (p < 0.001). Angiotensin 2 receptor (AT2R) (p = 0.0024), phosphorylated 5′-AMP-activated protein kinase (AMPKα) (p < 0.0124) and peroxisome proliferator-activated receptor gamma (PPARγ) (p < 0.001) were enhanced in skeletal muscle of IRW45-treated mice, as was the expression of genes involved in myogenesis. Plasma angiotensin converting enzyme-2 (ACE2) activity was increased (p = 0.0016). Uncoupling protein-1 in white adipose tissue (WAT) was partially restored after IRW supplementation. IRW improves glucose tolerance and body composition in HFD-fed mice and promotes glucose uptake in skeletal muscle via multiple signaling pathways, independent of angiotensin converting enzyme (ACE) inhibition.

Genetic Landscape of the ACE2 Coronavirus Receptor.

Background:SARS-CoV-2, the causal agent of COVID-19, enters human cells using the ACE2 (angiotensin-converting enzyme 2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart and respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biological systems. However, the genetic basis of the ACE2 protein levels is not well understood.Methods:We have conducted the largest genome-wide association meta-analysis of plasma ACE2 levels in >28 000 individuals of the SCALLOP Consortium (Systematic and Combined Analysis of Olink Proteins). We summarize the cross-sectional epidemiological correlates of circulating ACE2. Using the summary statistics–based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 severity using mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data.Results:We identified 10 loci, including 8 novel, capturing 30% of the heritability of the protein. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis–protein quantitative trait loci–based mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10–2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05–2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08–2.37]; P=0.02). Tissue- and cell type–specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells.Conclusions:Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.

Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice.

Angiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, changes tissue levels of ACE2 in healthy male and female mice. Mice received lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both for 21 days via drinking water. A control group received water without drug. The ACE2 protein index (ACE2 protein/total protein) was determined on the small intestine, lung, kidney, and brain. Oral lisinopril increased the ACE2 protein index across all tissues (p < 0.0001 vs. control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue (p = 0.89 vs. control) and even decreased tissue expression of the Ace2 gene (p < 0.001 vs. control). Tissue ACE2 remained elevated in the mice 21 days after cessation of lisinopril (p = 0.02). Plasma ACE2 did not correlate with the ACE2 protein index in any tissue. A sex difference was observed: kidney ACE2 levels were higher in male than in female mice (p < 0.0001). Oral lisinopril increases ACE2, the cellular receptor for SARS-CoV-2, in tissues that are relevant to the transmission and pathogenesis of COVID-19. Remarkably, the addition of losartan prevented lisinopril-induced increases in ACE2 across tissues. These results suggest that ACE inhibitors and angiotensin receptor blockers interact to determine tissue levels of ACE2.

Circulating Angiotensin Converting Enzyme 2 Activity in Hospitalised Patients With Acute Heart Failure

Angiotensin-converting enzyme 2 (ACE2) is present on endothelial cells with a role to degrade angiotensin II. In this study, we investigate plasma ACE2 levels in patients admitted with acute heart failure (AHF) and determine if levels differ according to ejection fraction (EF).

Vitamin D association with the renin angiotensin system in polycystic ovary syndrome

Vitamin D deficiency is a negative endocrine renin-angiotensin system (RAS) modulator and PCOS women are often vitamin D deficient, leading to RAS overactivation in PCOS.A cross-sectional study was performed in 99 PCOS and 68 control women who presented sequentially. Circulating plasma levels of RAS proteins (Angiotensin-converting enzyme 2 (ACE2), renin and angiotensinogen) were measured by Slow Off-rate Modified Aptamer (SOMA)-scan and 25-hydroxyvitamin D [25(OH)D] was measured by tandem mass spectroscopy.The RAS system was found to be overactivated in the PCOS women compared to non-PCOS control women with increased renin and decreased angiotensinogen (p < 0.05); 25-hydroxyvitamin D was also significantly lower in the PCOS group (p < 0.0001). In PCOS women, plasma renin was increased in vitamin D deficient and insufficient groups compared with the vitamin D sufficient group (p < 0.005), but did not differ across non-PCOS control subgroups. In non-PCOS controls, plasma ACE2 decreased from vitamin D insufficiency to deficiency (p < 0.05). Angiotensinogen was not different across the vitamin D sufficiency, insufficiency and deficiency strata for either PCOS or non-PCOS controls.These data show that RAS activation through increased plasma renin levels was seen in vitamin D insufficient and deficient PCOS subjects compared to non-PCOS control women. In addition, decreased plasma ACE2 levels were seen in vitamin D deficiency in non-PCOS controls, which may predispose these vitamin D deficient subjects to increased cardiovascular risk and susceptibility to infectious agents such as COVID-19 where this is a risk factor.

Distinct Regulation of U-ACE2 and P-ACE2 (Urinary and Plasma Angiotensin-Converting Enzyme 2) in a Japanese General Population.

[Figure: see text].

Plasma ACE2 species are differentially altered in COVID-19 patients.

Studies are needed to identify useful biomarkers to assess the severity and prognosis of COVID‐19 disease, caused by severe acute respiratory syndrome coronavirus (SARS‐CoV‐2) virus. Here, we examine the levels of various plasma species of the SARS‐CoV‐2 host receptor, the angiotensin‐converting enzyme 2 (ACE2), in patients at different phases of the infection. Human plasma ACE2 species were characterized by immunoprecipitation and western blotting employing antibodies against the ectodomain and the C‐terminal domain, using a recombinant human ACE2 protein as control. In addition, changes in the cleaved and full‐length ACE2 species were also examined in serum samples derived from humanized K18‐hACE2 mice challenged with a lethal dose of SARS‐CoV‐2. ACE2 immunoreactivity was present in human plasma as several molecular mass species that probably comprise truncated (70 and 75 kDa) and full‐length forms (95, 100, 130, and 170 kDa). COVID‐19 patients in the acute phase of infection (n = 46) had significantly decreased levels of ACE2 full‐length species, while a truncated 70‐kDa form was marginally higher compared with non‐disease controls (n = 26). Levels of ACE2 full‐length species were in the normal range in patients after a recovery period with an interval of 58‐70 days (n = 29), while the 70‐kDa species decreased. Levels of the truncated ACE2 species served to discriminate between individuals infected by SARS‐CoV‐2 and those infected with influenza A virus (n = 17). In conclusion, specific plasma ACE2 species are altered in patients with COVID‐19 and these changes normalize during the recovery phase. Alterations in ACE2 species following SARS‐CoV‐2 infection warrant further investigation regarding their potential usefulness as biomarkers for the disease process and to asses efficacy during vaccination.

Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). Here, we investigate associations between plasma ACE2 and outcome of COVID-19. This analysis used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort). Comprehensive clinical data were collected on this cohort, including 28-day outcomes. The samples were run on the Olink® Explore 1536 platform which includes measurement of the ACE2 protein. High admission plasma ACE2 in COVID-19 patients was associated with increased maximal illness severity within 28 days with OR = 1.8, 95%-CI: 1.4-2.3 (P < 0.0001). Plasma ACE2 was significantly higher in COVID-19 patients with hypertension compared with patients without hypertension (P = 0.0045). Circulating ACE2 was also significantly higher in COVID-19 patients with pre-existing heart conditions and kidney disease compared with patients without these pre-existing conditions (P = 0.0363 and P = 0.0303, respectively). This study suggests that measuring plasma ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 could be a link between COVID-19 illness severity and its established risk factors hypertension, pre-existing heart disease and pre-existing kidney disease.

Low plasma angiotensin-converting enzyme 2 level in diabetics increases the risk of severe COVID-19 infection.

Patients with pre-existing chronic diseases are more susceptible to coronavirus disease 2019 (COVID-19), yet the underlying causes of increased risk are of infection remain unclear. Angiotensin-converting- enzyme 2 (ACE2), the cell surface receptor that recognizes the coronavirus spike protein has protective effects against inflammation and chronic hyperglycemia in animal models. The roles of ACE2 in severe SARS-CoV-2 infections remains ambiguous due to contradictory findings. In this study, we aimed to investigate the relationship between human plasma ACE2 levels in diabetics and the high risk of severe SARS-CoV-2 infection. First, the medical records of 245 patients with SARS-CoV-2-positive who have chronic diseases were analyzed. We also recruited 404 elderly subjects with comorbid chronic diseases such as diabetes mellitus, coronary heart disease, cerebrovascular disease, hypertension and obesity, and investigated the ACE2 plasma levels. Plasma concentrations of ACE2 were much lower (2973.83±2196.79 pg/mL) in diabetics with chronic disease than in healthy controls (4308.21±2352.42 pg/ml), and the use of hypoglycemia drugs was associated with lower circulating concentrations of ACE2 (P=1.49E-08). Diabetics with lower plasma levels of ACE2 may be susceptible to severe COVID-19. Our findings suggest that the poor prognosis in patients with diabetes infected with SARS-CoV-2 may be due to low circulating ACE2 levels.