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1.
Life Sci Alliance ; 5(2)2022 02.
Article in English | MEDLINE | ID: covidwho-1547941

ABSTRACT

The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration of antiviral antibodies and by their affinity to their targets. However, the affinity of polyclonal antibody responses in plasma is difficult to measure. Here we used microfluidic antibody affinity profiling (MAAP) to determine the aggregate affinities and concentrations of anti-SARS-CoV-2 antibodies in plasma samples of 42 seropositive individuals, 19 of which were healthy donors, 20 displayed mild symptoms, and 3 were critically ill. We found that dissociation constants, K d, of anti-receptor-binding domain antibodies spanned 2.5 orders of magnitude from sub-nanomolar to 43 nM. Using MAAP we found that antibodies of seropositive individuals induced the dissociation of pre-formed spike-ACE2 receptor complexes, which indicates that MAAP can be adapted as a complementary receptor competition assay. By comparison with cytopathic effect-based neutralisation assays, we show that MAAP can reliably predict the cellular neutralisation ability of sera, which may be an important consideration when selecting the most effective samples for therapeutic plasmapheresis and tracking the success of vaccinations.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , Microfluidics/methods , SARS-CoV-2/immunology , Adult , Aged , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Viral/immunology , Antibody Affinity , B-Lymphocytes/immunology , B-Lymphocytes/virology , COVID-19/blood , COVID-19/etiology , Cross Reactions , Female , Humans , Male , Middle Aged , Severity of Illness Index , Spike Glycoprotein, Coronavirus/blood , Spike Glycoprotein, Coronavirus/immunology , Surface Plasmon Resonance
2.
Biomark Med ; 15(17): 1581-1588, 2021 12.
Article in English | MEDLINE | ID: covidwho-1496869

ABSTRACT

Introduction: SARS-CoV-2 requires angiotensin-converting enzyme 2 (ACE2) to enter the cell. In our study, we aimed to investigate the role of angiotensin-converting enzyme 2 and angiotensin II plasma levels on prognosis and mortality in patients with isolated hypertension, patients with chronic diseases in addition to hypertension and patients with COVID-19 without comorbidities, in accordance with the use of renin-angiotensin-aldosterone system inhibitor. Materials & methods: In the study, patients diagnosed with COVID-19 were divided into three groups. Angiotensin II and ACE2 levels were compared by comorbidities, antihypertensive drugs used, intensive care hospitalization and termination of patients. The relationship between angiotensin II and ACE2 levels and service and intensive care times was investigated. Findings: A total of 218 patients were enrolled in our study, including 68 patients diagnosed with COVID-19 without comorbidities, 33 patients diagnosed with isolated hypertension and 117 patients with other chronic diseases in addition to hypertension. There was no statistically significant difference between the comorbid disease groups between angiotensin II and ACE2 levels of the patients enrolled in the study. The rate of patients admitted to the intensive care unit was 17.9%, and the mortality rate was 11.5%. Results: In our study, we did not obtain significant findings regarding angiotensin II and ACE2 levels on presentation that can be used in prognosis and mortality of COVID-19 patients and development of future treatment methods.


Subject(s)
Angiotensin II/blood , Angiotensin-Converting Enzyme 2/blood , COVID-19 , Hypertension , SARS-CoV-2/metabolism , Adult , Aged , Aged, 80 and over , COVID-19/blood , COVID-19/mortality , Disease-Free Survival , Female , Humans , Hypertension/blood , Hypertension/mortality , Male , Middle Aged , Prospective Studies , Survival Rate
3.
Int J Biol Macromol ; 193(Pt A): 948-955, 2021 Dec 15.
Article in English | MEDLINE | ID: covidwho-1471998

ABSTRACT

The severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) keeps on destroying normal social integrity worldwide, bringing about extraordinary medical services, cultural and financial interruption. Individuals with diabetes have been demonstrated to be at higher risk of complications and even death when exposed to SARS-CoV-2. Regardless of pandemic scale infection, there is presently limited comprehension on the potential impact of SARS-CoV-2 on individuals with diabetes. Human serum albumin (HSA) is the most abundant circulating plasma protein in human serum and attracted more interest from researchers because most susceptible to non-enzymatic glycation reactions. Albumin down-regulates the expression of ACE2 that is the target receptor of COVID-19. Hypoalbuminemia, coagulopathy, and vascular disease have been connected in COVID-19 and appear to predict outcomes independent of age and morbidity. This review discusses the most recent evidence that the ACE/ACE2 ratio could influence by human serum albumin both the susceptibility of individuals to SARS-CoV-2 infection and the outcome of the COVID-19 disease.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19 , SARS-CoV-2/metabolism , Serum Albumin, Human/metabolism , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/therapy , COVID-19/blood , COVID-19/diagnosis , COVID-19/therapy , Disease Susceptibility , Humans , Vascular Diseases/blood , Vascular Diseases/diagnosis , Vascular Diseases/therapy
4.
J Steroid Biochem Mol Biol ; 214: 105965, 2021 11.
Article in English | MEDLINE | ID: covidwho-1454329

ABSTRACT

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.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , Angiotensinogen/blood , Polycystic Ovary Syndrome/blood , Renin/blood , Vitamin D Deficiency/blood , Adult , Blood Pressure , Female , Humans , Polycystic Ovary Syndrome/physiopathology , Renin-Angiotensin System , Vitamin D/blood , Vitamin D Deficiency/physiopathology , Vitamins/blood , Young Adult
5.
J Med Virol ; 93(10): 5908-5916, 2021 10.
Article in English | MEDLINE | ID: covidwho-1432424

ABSTRACT

The main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 interactions with ACE2 may increase ectodomain shedding but consequences for the renin-angiotensin system and pathology in Coronavirus disease 2019 (COVID-19) remain unclear. We measured soluble ACE2 (sACE2) and sACE levels by enzyme-linked immunosorbent assay in 114 hospital-treated COVID-19 patients compared with 10 healthy controls; follow-up samples after four months were analyzed for 58 patients. Associations between sACE2 respectively sACE and risk factors for severe COVID-19, outcome, and inflammatory markers were investigated. Levels of sACE2 were higher in COVID-19 patients than in healthy controls, median 5.0 (interquartile range 2.8-11.8) ng/ml versus 1.4 (1.1-1.6) ng/ml, p < .0001. sACE2 was higher in men than women but was not affected by other risk factors for severe COVID-19. sACE2 decreased to 2.3 (1.6-3.9) ng/ml at follow-up, p < .0001, but remained higher than in healthy controls, p = .012. sACE was marginally lower during COVID-19 compared with at follow-up, 57 (45-70) ng/ml versus 72 (52-87) ng/ml, p = .008. Levels of sACE2 and sACE did not differ depending on survival or disease severity. sACE2 during COVID-19 correlated with von Willebrand factor, factor VIII and D-dimer, while sACE correlated with interleukin 6, tumor necrosis factor α, and plasminogen activator inhibitor 1. Conclusions: sACE2 was transiently elevated in COVID-19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID-19 differed in correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , Adult , Aged , Biomarkers/blood , Female , Follow-Up Studies , Humans , Inflammation , Male , Middle Aged , Peptidyl-Dipeptidase A/blood , Renin-Angiotensin System , Risk Factors , SARS-CoV-2
9.
Front Immunol ; 12: 625732, 2021.
Article in English | MEDLINE | ID: covidwho-1291351

ABSTRACT

The etiological agent of COVID-19 SARS-CoV-2, is primarily a pulmonary-tropic coronavirus. Infection of alveolar pneumocytes by SARS-CoV-2 requires virus binding to the angiotensin I converting enzyme 2 (ACE2) monocarboxypeptidase. ACE2, present on the surface of many cell types, is known to be a regulator of blood pressure homeostasis through its ability to catalyze the proteolysis of Angiotensin II (Ang II) into Angiotensin-(1-7) [Ang-(1-7)]. We therefore hypothesized that SARS-CoV-2 could trigger variations of ACE2 expression and Ang II plasma concentration in SARS-CoV-2-infected patients. We report here, that circulating blood cells from COVID-19 patients express less ACE2 mRNA than cells from healthy volunteers. At the level of circulating cells, this ACE2 gene dysregulation mainly affects the monocytes, which also show a lower expression of membrane ACE2 protein. Moreover, soluble ACE2 (sACE2) plasma concentrations are lower in prolonged viral shedders than in healthy controls, while the concentration of sACE2 returns to normal levels in short viral shedders. In the plasma of prolonged viral shedders, we also found higher concentrations of Ang II and angiotensin I (Ang I). On the other hand, the plasma levels of Ang-(1-7) remains almost stable in prolonged viral shedders but seems insufficient to prevent the adverse effects of Ang II accumulation. Altogether, these data evidence that the SARS-CoV-2 may affect the expression of blood pressure regulators with possible harmful consequences on COVID-19 outcome.


Subject(s)
Angiotensin II/blood , Angiotensin I/blood , Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , Peptide Fragments/blood , Adult , Angiotensin-Converting Enzyme 2/genetics , COVID-19/virology , Female , Gene Expression Profiling , HLA-DR Antigens , Humans , Lipopolysaccharide Receptors , Male , Middle Aged , Monocytes/immunology , Monocytes/metabolism , Pilot Projects , Prospective Studies , RNA, Messenger , Virus Shedding
10.
FASEB J ; 35(8): e21745, 2021 08.
Article in English | MEDLINE | ID: covidwho-1288103

ABSTRACT

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.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/cerebrospinal fluid , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/urine , Biomarkers/blood , Brain Chemistry , Colon/chemistry , Female , Humans , Liver/chemistry , Male , Middle Aged , Saliva/chemistry
11.
Int J Mol Sci ; 22(11)2021 Jun 07.
Article in English | MEDLINE | ID: covidwho-1259510

ABSTRACT

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).


Subject(s)
Aging/genetics , COVID-19/genetics , COVID-19/physiopathology , CpG Islands , Telomere Shortening , Telomere/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2/blood , Biomarkers , COVID-19/complications , COVID-19/etiology , DNA Methylation , Dipeptidyl Peptidase 4/blood , Epigenomics , Female , High-Throughput Nucleotide Sequencing , Host Microbial Interactions , Humans , Male , Middle Aged , Risk Factors , Survivors
12.
PLoS One ; 16(6): e0252799, 2021.
Article in English | MEDLINE | ID: covidwho-1259248

ABSTRACT

AIMS: 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. METHODS AND RESULTS: 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). CONCLUSION: 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.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19 , Heart Diseases , Hospitalization , Kidney Diseases , SARS-CoV-2/metabolism , Adolescent , Adult , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Comorbidity , Female , Heart Diseases/blood , Heart Diseases/mortality , Heart Diseases/therapy , Humans , Kidney Diseases/blood , Kidney Diseases/mortality , Kidney Diseases/therapy , Male , Middle Aged , Severity of Illness Index
13.
Am J Gastroenterol ; 116(8): 1638-1645, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1248431

ABSTRACT

INTRODUCTION: Proton pump inhibitor (PPI) use was recently reported to be associated with increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and worse clinical outcomes. The underlying mechanism(s) for this association are unclear. METHODS: We performed a prospective study of hospitalized coronavirus disease 2019 (COVID-19) patients and COVID-negative controls to understand how PPI use may affect angiotensin-converting enzyme 2 (ACE2) expression and stool SARS-CoV-2 RNA. Analysis of a retrospective cohort of hospitalized patients with COVID-19 from March 15, 2020 to August 15, 2020 in 6 hospitals was performed to evaluate the association of PPI use and mortality. Covariates with clinical relevance to COVID-19 outcomes were included to determine predictors of in-hospital mortality. RESULTS: Control PPI users had higher salivary ACE2 mRNA levels than nonusers, 2.39 ± 1.15 vs 1.22 ± 0.92 (P = 0.02), respectively. Salivary ACE2 levels and stool SARS-CoV-2 RNA detection rates were comparable between users and nonusers of PPI. In 694 hospitalized patients with COVID-19 (age = 58 years, 46% men, and 65% black), mortality rate in PPI users and nonusers was 30% (68/227) vs 12.1% (53/439), respectively. Predictors of mortality by logistic regression were PPI use (adjusted odds ratio [aOR] = 2.72, P < 0.001), age (aOR = 1.66 per decade, P < 0.001), race (aOR = 3.03, P = 0.002), cancer (aOR = 2.22, P = 0.008), and diabetes (aOR = 1.95, P = 0.003). The PPI-associated mortality risk was higher in black patients (aOR = 4.16, 95% confidence interval: 2.28-7.59) than others (aOR = 1.62, 95% confidence interval: 0.82-3.19, P = 0.04 for interaction). DISCUSSION: COVID-negative PPI users had higher salivary ACE2 expression. PPI use was associated with increased mortality risk in patients with COVID-19, particularly African Americans.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , COVID-19/mortality , Proton Pump Inhibitors/adverse effects , Adult , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , Retrospective Studies , Risk Assessment
14.
Int J Mol Sci ; 22(10)2021 May 17.
Article in English | MEDLINE | ID: covidwho-1234744

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic was associated with multiple organ failure and comorbidities, such as type 2 diabetes mellitus (T2DM). Risk factors, such as age, gender, and obesity, were associated with COVID-19 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to use several host receptors for viral entry, such as angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the lung and other organs. However, ACE2 could be shed from the surface to be soluble ACE2 (sACE2) in the circulation. The epigenetic factors affecting ACE2 expression include a type of small non-coding RNAs called microRNAs (miRNAs). In this study, we aimed at exploring the status of the sACE2 as well as serum levels of several upstream novel miRNAs as non-invasive biomarkers that might have a potential role in T2DM patients. Serum samples were collected from 50 T2DM patients and 50 healthy controls, and sACE2 levels were quantified using enzyme-linked immunosorbent assay (ELISA). Also, RNA was extracted, and TaqMan miRNA reverse transcription quantitative PCR (RT-qPCR) was performed to measure serum miRNA levels. Our results revealed that sACE2 is decreased in the T2DM patients and is affected by age, gender, and obesity level. Additionally, 4 miRNAs, which are revealed by in silico analysis to be potentially upstream of ACE2 were detectable in the serum. Among them, miR-421 level was found to be decreased in the serum of diabetic patients, regardless of the presence or absence of diabetic complications, as well as being differential in various body mass index (BMI) groups. The other 3 miRNAs (miR-3909, miR-212-5p, and miR-4677-3p) showed associations with multiple factors including age, gender, BMI, and serum markers, in addition to being correlated to each other. In conclusion, our study reveals a decline in the circulating serum levels of sACE2 in T2DM patients and identified 4 novel miRNAs that were associated with T2DM, which are influenced by different clinical and demographic factors.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , Diabetes Complications/blood , Diabetes Mellitus, Type 2/blood , MicroRNAs/blood , Adult , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Biomarkers/blood , Body Mass Index , COVID-19/blood , COVID-19/complications , COVID-19/genetics , Diabetes Complications/genetics , Diabetes Complications/virology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/virology , Down-Regulation , Female , Gene Expression Regulation/genetics , Humans , Male , MicroRNAs/genetics , Middle Aged , Obesity/blood , Obesity/genetics
15.
Am J Physiol Lung Cell Mol Physiol ; 321(1): L213-L218, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1234311

ABSTRACT

The renin-angiotensin system (RAS) is fundamental to COVID-19 pathobiology, due to the interaction between the SARS-CoV-2 virus and the angiotensin-converting enzyme 2 (ACE2) coreceptor for cellular entry. The prevailing hypothesis is that SARS-CoV-2-ACE2 interactions lead to an imbalance of the RAS, favoring proinflammatory angiotensin II (ANG II)-related signaling at the expense of the anti-inflammatory ANG-(1-7)-mediated alternative pathway. Indeed, multiple clinical trials targeting this pathway in COVID-19 are underway. Therefore, precise measurement of circulating RAS components is critical to understand the interplay of the RAS on COVID-19 outcomes. Multiple challenges exist in measuring the RAS in COVID-19, including improper patient controls, ex vivo degradation and low concentrations of angiotensins, and unvalidated laboratory assays. Here, we conducted a prospective pilot study to enroll 33 patients with moderate and severe COVID-19 and physiologically matched COVID-19-negative controls to quantify the circulating RAS. Our enrollment strategy led to physiological matching of COVID-19-negative and COVID-19-positive moderate hypoxic respiratory failure cohorts, in contrast to the severe COVID-19 cohort, which had increased severity of illness, prolonged intensive care unit (ICU) stay, and increased mortality. Circulating ANG II and ANG-(1-7) levels were measured in the low picomolar (pM) range. We found no significant differences in circulating RAS peptides or peptidases between these three cohorts. The combined moderate and severe COVID-19-positive cohorts demonstrated a mild reduction in ACE activity compared with COVID-19-negative controls (2.2 ± 0.9 × 105 vs. 2.9 ± 0.8 × 105 RFU/mL, P = 0.03). These methods may be useful in designing larger studies to physiologically match patients and quantify the RAS in COVID-19 RAS augmenting clinical trials.


Subject(s)
Angiotensin II/blood , Angiotensin I/blood , Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , Peptide Fragments/blood , Renin-Angiotensin System , Respiratory Insufficiency/blood , SARS-CoV-2/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/physiopathology , Female , Humans , Male , Middle Aged , Pilot Projects , Respiratory Insufficiency/pathology , Respiratory Insufficiency/physiopathology
16.
Aging (Albany NY) ; 13(9): 12301-12307, 2021 05 06.
Article in English | MEDLINE | ID: covidwho-1220256

ABSTRACT

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.


Subject(s)
Angiotensin-Converting Enzyme 2/blood , COVID-19/blood , Diabetes Mellitus/blood , Aged , COVID-19/enzymology , Diabetes Mellitus/enzymology , Female , Humans , Male , Middle Aged , SARS-CoV-2
17.
Int J Mol Sci ; 22(9)2021 Apr 25.
Article in English | MEDLINE | ID: covidwho-1202187

ABSTRACT

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.


Subject(s)
COVID-19/pathology , Hyperandrogenism/pathology , Polycystic Ovary Syndrome/pathology , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/urine , Animals , Blood Glucose/analysis , Body Weight/drug effects , COVID-19/complications , COVID-19/virology , Cathepsin L/genetics , Cathepsin L/metabolism , Dihydrotestosterone/pharmacology , Female , Humans , Kidney/metabolism , Mice , Mice, Inbred C57BL , Polycystic Ovary Syndrome/complications , SARS-CoV-2/isolation & purification , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Up-Regulation/drug effects , Virus Internalization
18.
Nutrients ; 13(4)2021 Apr 14.
Article in English | MEDLINE | ID: covidwho-1187014

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for one of the worst pandemics in modern history. Several prevention and treatment strategies have been designed and evaluated in recent months either through the repurposing of existing treatments or the development of new drugs and vaccines. In this study, we show that L-carnitine tartrate supplementation in humans and rodents led to significant decreases of key host dependency factors, notably angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and Furin, which are responsible for viral attachment, viral spike S-protein cleavage, and priming for viral fusion and entry. Interestingly, pre-treatment of Calu-3, human lung epithelial cells, with L-carnitine tartrate led to a significant and dose-dependent inhibition of the infection by SARS-CoV-2. Infection inhibition coincided with a significant decrease in ACE2 mRNA expression levels. These data suggest that L-carnitine tartrate should be tested with appropriate trials in humans for the possibility to limit SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , Carnitine/administration & dosage , Tartrates/administration & dosage , Adult , Aged , Angiotensin-Converting Enzyme 2/blood , Animals , COVID-19/metabolism , Carnitine/pharmacology , Cell Line , Cell Survival/drug effects , Female , Furin/blood , Furin/metabolism , Humans , Inflammation/metabolism , Male , Middle Aged , Rats , SARS-CoV-2 , Serine Endopeptidases/blood , Serine Endopeptidases/metabolism , Tartrates/pharmacology , Young Adult
19.
J Zhejiang Univ Sci B ; 22(4): 330-340, 2021 Apr 15.
Article in English | MEDLINE | ID: covidwho-1175476

ABSTRACT

Epidemiological evidence suggests that patients with hypertension infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at increased risk of acute lung injury. However, it is still not clear whether this increased risk is related to the usage of renin-angiotensin system (RAS) blockers. We collected medical records of coronavirus disease 2019 (COVID-19) patients from the First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou, China), and evaluated the potential impact of an angiotensin II receptor blocker (ARB) on the clinical outcomes of COVID-19 patients with hypertension. A total of 30 hypertensive COVID-19 patients were enrolled, of which 17 were classified as non-ARB group and the remaining 13 as ARB group based on the antihypertensive therapies they received. Compared with the non-ARB group, patients in the ARB group had a lower proportion of severe cases and intensive care unit (ICU) admission as well as shortened length of hospital stay, and manifested favorable results in most of the laboratory testing. Viral loads in the ARB group were lower than those in the non-ARB group throughout the disease course. No significant difference in the time of seroconversion or antibody levels was observed between the two groups. The median levels of soluble angiotensin-converting enzyme 2 (sACE2) in serum and urine samples were similar in both groups, and there were no significant correlations between serum sACE2 and biomarkers of disease severity. Transcriptional analysis showed 125 differentially expressed genes which mainly were enriched in oxygen transport, bicarbonate transport, and blood coagulation. Our results suggest that ARB usage is not associated with aggravation of COVID-19. These findings support the maintenance of ARB treatment in hypertensive patients diagnosed with COVID-19.


Subject(s)
Angiotensin Receptor Antagonists/therapeutic use , Antibodies, Viral/blood , COVID-19/complications , Hypertension/drug therapy , Viral Load , Aged , Aged, 80 and over , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme 2/blood , Antihypertensive Agents/adverse effects , Antihypertensive Agents/therapeutic use , Biomarkers , China , Female , Humans , Hypertension/complications , Intensive Care Units , Length of Stay , Male , Middle Aged , Retrospective Studies , Transcriptome
20.
Environ Toxicol Pharmacol ; 86: 103656, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1171468

ABSTRACT

Evidence in humans suggests a correlation between nicotine smoking and severe respiratory symptoms with COVID-19 infection. In lung tissue, angiotensin-converting enzyme 2 (ACE2) appears to mechanistically underlie viral entry. Here, we investigated whether e-cigarette vapor inhalation alters ACE2 and nicotinic acetylcholine receptor (nAChR) expression in male and female mice. In male lung, nicotine vapor inhalation induced a significant increase in ACE2 mRNA and protein, but surprisingly, these differences were not found in females. Further, both vehicle and nicotine vapor inhalation downregulated α5 nAChR subunits in both sexes, while differences were not found in α7 nAChR subunit expression. Finally, blood ACE2 levels did not differ with exposure, indicating that blood sampling is not a sufficient indicator of lung ACE2 changes. Together, these data indicate a direct link between e-cigarette vaping and increased ACE2 expression in male lung tissue, which thereby reveals an underlying mechanism of increased vulnerability to coronavirus infection in individuals vaping nicotine.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/epidemiology , Electronic Nicotine Delivery Systems , Lung/enzymology , Vaping/adverse effects , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/genetics , Animals , DNA, Complementary/biosynthesis , Female , Lung/cytology , Male , Mice , Mice, Inbred C57BL , Nicotine/administration & dosage , Nicotine/pharmacology , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/biosynthesis , Sex Characteristics , alpha7 Nicotinic Acetylcholine Receptor/metabolism
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