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1.
Front Endocrinol (Lausanne) ; 12: 725967, 2021.
Article in English | MEDLINE | ID: covidwho-1506113

ABSTRACT

The renin-angiotensin system (RAS) is crucially involved in the physiology and pathology of all organs in mammals. Angiotensin-converting enzyme 2 (ACE2), which is a homolog of ACE, acts as a negative regulator in the homeostasis of RAS. ACE2 has been proven to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic. As SARS-CoV-2 enters the host cells through binding of viral spike protein with ACE2 in humans, the distribution and expression level of ACE2 may be critical for SARS-CoV-2 infection. Growing evidence shows the implication of ACE2 in pathological progression in tissue injury and several chronic conditions such as hypertension, diabetes, and cardiovascular disease; this suggests that ACE2 is essential in the progression and clinical prognosis of COVID-19 as well. Therefore, we summarized the expression and activity of ACE2 under various conditions and regulators. We further discussed its potential implication in susceptibility to COVID-19 and its potential for being a therapeutic target in COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/prevention & control , Peptidyl-Dipeptidase A/physiology , Renin-Angiotensin System/physiology , COVID-19/drug therapy , COVID-19/epidemiology , Humans , Molecular Targeted Therapy , Pandemics , SARS-CoV-2
2.
Mayo Clin Proc ; 95(7): 1354-1368, 2020 07.
Article in English | MEDLINE | ID: covidwho-1500136

ABSTRACT

OBJECTIVE: To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. PATIENTS AND METHODS: RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020. RESULTS: Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value =1.30×10-23), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P=5.22×10-4), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P=1.66×10-6). CONCLUSION: More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart.


Subject(s)
Betacoronavirus , Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/virology , Coronavirus Infections/complications , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Adolescent , Adult , Aged , Angiotensin-Converting Enzyme 2 , COVID-19 , Cardiomyopathy, Hypertrophic/metabolism , Case-Control Studies , Child , Genotype , Humans , Middle Aged , Myocardium/metabolism , Pandemics , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , Young Adult
3.
Am J Respir Crit Care Med ; 204(9): 1024-1034, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1495777

ABSTRACT

Rationale: ACE2 (angiotensin-converting enzyme 2), the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is expressed in type 2 alveolar epithelial cells (AT2) that may play key roles in postinjury repair. An imbalance between ACE2 and ACE has also been hypothesized to contribute to lung injury. Objectives: To characterize the expression and distribution of ACE2 and ACE and to compare AT2 with endothelial cell expression in coronavirus disease (COVID-19)-related or -unrelated acute respiratory distress syndrome (ARDS) and controls. Methods: Lung tissue stainings (using multiplex immunofluorescence) and serum concentrations of ACEs were determined retrospectively in two different cohorts of patients. AT2 and endothelial cells were stained in lung tissue for ProSPC (pro-surfactant protein C) and CD31, respectively. Measurements and Main Results: Pulmonary ACE2 expression was increased in patients with COVID-19-related and -unrelated ARDS (0.06% of tissue area and 0.12% vs. 0.006% for control subjects; P = 0.013 and P < 0.0001, respectively). ACE2 was upregulated in endothelial cells (0.32% and 0.53% vs. 0.01%; P = 0.009 and P < 0.0001) but not in AT2 cells (0.13% and 0.08% vs. 0.03%; P = 0.94 and P = 0.44). Pulmonary expression of ACE was decreased in both COVID-19-related and -unrelated ARDS (P = 0.057 and P = 0.032). Similar increases in ACE2 and decreases in ACE were observed in sera of COVID-19 (P = 0.0054 and P < 0.0001) and non-COVID-19 ARDS (P < 0.0001 and P = 0.016). In addition, AT2 cells were decreased in patients with COVID-19-related ARDS compared with COVID-19-unrelated ARDS (1.395% vs. 2.94%, P = 0.0033). Conclusions: ACE2 is upregulated in lung tissue and serum of both COVID-19-related and -unrelated ARDS, whereas a loss of AT2 cells is selectively observed in COVID-19-related ARDS.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Respiratory Distress Syndrome/metabolism , Adult , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/physiopathology , Case-Control Studies , Female , Humans , Immunohistochemistry , Logistic Models , Male , Middle Aged , Proportional Hazards Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/virology , Retrospective Studies , Severity of Illness Index , Up-Regulation
4.
J Thorac Oncol ; 16(11): 1821-1839, 2021 11.
Article in English | MEDLINE | ID: covidwho-1492352

ABSTRACT

INTRODUCTION: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2. METHODS: Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. RESULTS: We find that ACE2 expression is restricted to a select population of epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium induces metabolic and transcriptional changes consistent with epithelial-to-mesenchymal transition (EMT), including up-regulation of ZEB1 and AXL, resulting in an increased EMT score. In addition, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT through the transforming growth factor-ß, ZEB1 overexpression, and onset of EGFR tyrosine kinase inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL inhibition and ZEB1 reduction, as with bemcentinib, offer a potential strategy to reverse this effect. CONCLUSIONS: These observations highlight the use of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses and offer important insights into the potential mechanisms underlying the morbidity and mortality of coronavirus disease 2019 in healthy patients and patients with cancer alike.


Subject(s)
COVID-19 , Lung Neoplasms , Bronchi , Humans , Lung , Peptidyl-Dipeptidase A , SARS-CoV-2
5.
Int J Mol Sci ; 22(21)2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1488613

ABSTRACT

The renin-angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a receptor to enter cells. Despite some controversies, numerous studies have reported a significant association between the use of ACE inhibitors and reduced risk of COVID-19. In our previous studies, we produced and identified peptide sequences present in whey hydrolysates exhibiting high ACE inhibitory activity. Therefore, the aim of this work is to obtain an improved understanding of the function of these natural peptides as RAS inhibitors and investigate their potential therapeutic role in the COVID-19 pandemic. The molecular interactions between peptides IPP, LIVTQ, IIAE, LVYPFP, and human ACE2 were assessed by employing a molecular docking approach. The results show that natural whey-derived peptides have a dual inhibitory action against both ACE and ACE2. This dual activity distinguishes these ACE inhibitory peptides from synthetic drugs, such as Captopril and Lisinopril which were not shown to inhibit ACE2 activity, and may represent a potential strategy in the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Peptides/chemistry , Peptides/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme Inhibitors/chemistry , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Peptides/metabolism , Peptidyl-Dipeptidase A/chemistry , Renin-Angiotensin System/drug effects , Whey Proteins/chemistry
6.
PLoS One ; 16(9): e0257016, 2021.
Article in English | MEDLINE | ID: covidwho-1484849

ABSTRACT

BACKGROUND: Activation of the immune system is implicated in the Post-Acute Sequelae after SARS-CoV-2 infection (PASC) but the mechanisms remain unknown. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) resulting in decreased activation of the AT1 receptor and decreased immune system activation. We hypothesized that autoantibodies against ACE2 may develop after SARS-CoV-2 infection, as anti-idiotypic antibodies to anti-spike protein antibodies. METHODS AND FINDINGS: We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS-CoV-2 infection and 13 with no history of infection. None of the 13 patients without history of SARS-CoV-2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS-CoV-2 had levels of ACE2 antibodies above the cutoff threshold. In contrast, 26/32 (81%) in the convalescent group and 14/15 (93%) of patients acutely hospitalized had detectable ACE2 antibodies. Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies. We measured the capacity of the samples to inhibit ACE2 enzyme activity. Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies. CONCLUSIONS: Many patients with a history of SARS-CoV-2 infection have antibodies specific for ACE2. Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma. Plasma from these patients also inhibits exogenous ACE2 activity. These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS-CoV-2 infection and decrease ACE2 activity. This could lead to an increase in the abundance of Ang II, which causes a proinflammatory state that triggers symptoms of PASC.


Subject(s)
Autoantibodies/blood , COVID-19/immunology , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/blood , Angiotensin II/blood , Angiotensin II/immunology , Angiotensin-Converting Enzyme 2/genetics , Autoantibodies/immunology , Autoantibodies/isolation & purification , COVID-19/blood , COVID-19/virology , Female , Humans , Male , Peptidyl-Dipeptidase A/blood , Receptor, Angiotensin, Type 1/blood , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/immunology , Renin-Angiotensin System/genetics , Renin-Angiotensin System/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/isolation & purification
7.
Cell Transplant ; 30: 9636897211049814, 2021.
Article in English | MEDLINE | ID: covidwho-1484237

ABSTRACT

During the past 18 months as the world dealt with the COVID-19 pandemic, articles published in Cell Transplantation (CT) voiced unique perspectives on the disease which have since been supported by additional research. Intrigued by the variability in COVID-19 severity, CT authors explored the influence of variants in angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) genes, as well as the role of androgen receptors on disease development. Mesenchymal stem cells (MSC) were offered up as a potential COVID-19 therapy because of their immune modulating characteristics and successful use in other acute respiratory diseases. Two CT author groups gave proof of principle when hospitalized COVID-19 patients were infused with MSC after no other interventions seemed to work. MSC treatment reduced disease severity and shortened hospitalization stays. Lastly, CT authors speculated why we are still in the midst of a pandemic and the consequences of disillusioned comfort as we face new emerging variants that may undermine all we have accomplished thus far.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Mesenchymal Stem Cells/cytology , Serine Endopeptidases/genetics , Angiotensin-Converting Enzyme 2/metabolism , Biomedical Research , Cell Transplantation , Cytokines/metabolism , Hospitalization , Humans , Immune System , Mesenchymal Stem Cells/metabolism , Peptidyl-Dipeptidase A/genetics , Publications , Receptors, Androgen/metabolism , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index
9.
Cells ; 10(10)2021 10 14.
Article in English | MEDLINE | ID: covidwho-1470799

ABSTRACT

The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.


Subject(s)
COVID-19/blood , COVID-19/metabolism , Renin-Angiotensin System , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Blood Pressure/drug effects , Humans , Peptidyl-Dipeptidase A/metabolism , Renin/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry
10.
Front Immunol ; 12: 728896, 2021.
Article in English | MEDLINE | ID: covidwho-1456291

ABSTRACT

A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNFα and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 µM reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1α and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNFα and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 µM) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 µM) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process. Graphical: Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Apoptosis/drug effects , COVID-19/immunology , Macrophages/immunology , Oxidative Stress/drug effects , Perindopril/pharmacology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/virology , Cell Line , Humans , Macrophages/drug effects , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pyroptosis/drug effects , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
11.
BMC Infect Dis ; 21(1): 901, 2021 Sep 03.
Article in English | MEDLINE | ID: covidwho-1455938

ABSTRACT

BACKGROUND: The detection of severe acute respiratory syndrome coronavirus (SARS-CoV-2) is challenging, particularly in post-mortem human tissues. However, there is increasing evidence for viral SARS-CoV-2 manifestation in non-respiratory tissues. In this context, it is a current matter of debate, whether SARS-CoV-2 shows hepatotropism. CASE PRESENTATION: Here, we report a case of an 88-year-old women with massive SARS-CoV-2 viremia, severe jaundice and clinical signs of an acute hepatitis, who died within a few days from an acute liver failure without showing any clinical signs of pneumonia. Autopsy revealed a severe chronic and acute liver damage with bile duct infestation by SARS-CoV-2 that was accompanied by higher expressions of angiotensin-converting enzyme-2 (ACE2), Cathepsin L and transmembrane serine protease 2 (TMPRSS2). CONCLUSION: Our findings indicate an enhanced biliary susceptibility to viral infection with SARS-CoV-2, that might have resulted from pre-existing severe liver damage. Furthermore, our findings emphasize the differential diagnosis of coronavirus disease 2019 (COVID-19)-associated liver failure in the clinical setting of an inexplicable jaundice.


Subject(s)
COVID-19 , Liver Failure, Acute , Aged, 80 and over , Female , Humans , Liver Cirrhosis/complications , Liver Failure, Acute/etiology , Peptidyl-Dipeptidase A , SARS-CoV-2
12.
J Clin Invest ; 131(19)2021 10 01.
Article in English | MEDLINE | ID: covidwho-1448084

ABSTRACT

BACKGROUNDThe angiotensin-converting enzyme (ACE) D allele is more prevalent among African Americans compared with other races and ethnicities and has previously been associated with severe coronavirus disease 2019 (COVID-19) pathogenesis through excessive ACE1 activity. ACE inhibitors/angiotensin receptor blockers (ACE-I/ARB) may counteract this mechanism, but their association with COVID-19 outcomes has not been specifically tested in the African American population.METHODSWe identified 6218 patients who were admitted into Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020, in New York City. We evaluated whether the outpatient and in-hospital use of ACE-I/ARB is associated with COVID-19 in-hospital mortality in an African American compared with non-African American population.RESULTSOf the 6218 patients with COVID-19, 1138 (18.3%) were ACE-I/ARB users. In a multivariate logistic regression model, ACE-I/ARB use was independently associated with a reduced risk of in-hospital mortality in the entire population (OR, 0.655; 95% CI, 0.505-0.850; P = 0.001), African American population (OR, 0.44; 95% CI, 0.249-0.779; P = 0.005), and non-African American population (OR, 0.748, 95% CI, 0.553-1.012, P = 0.06). In the African American population, in-hospital use of ACE-I/ARB was associated with improved mortality (OR, 0.378; 95% CI, 0.188-0.766; P = 0.006), whereas outpatient use was not (OR, 0.889; 95% CI, 0.375-2.158; P = 0.812). When analyzing each medication class separately, ARB in-hospital use was significantly associated with reduced in-hospital mortality in the African American population (OR, 0.196; 95% CI, 0.074-0.516; P = 0.001), whereas ACE-I use was not associated with impact on mortality in any population.CONCLUSIONIn-hospital use of ARB was associated with a significant reduction in in-hospital mortality among COVID-19-positive African American patients.FUNDINGNone.


Subject(s)
African Americans , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , COVID-19 , Hospital Mortality/ethnology , SARS-CoV-2/metabolism , Aged , COVID-19/drug therapy , COVID-19/ethnology , COVID-19/metabolism , COVID-19/mortality , Disease-Free Survival , Female , Humans , Male , Middle Aged , Peptidyl-Dipeptidase A/metabolism , Retrospective Studies , Survival Rate
13.
J Infect Public Health ; 14(11): 1686-1692, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1446871

ABSTRACT

As far as comorbidity is concerned, cardiovascular diseases (CVD) appear to be accounted for the highest prevalence, severity, and fatality among COVID 19 patients. A wide array of causal links connecting CVD and COVID-19 baffle the overall prognosis as well as the efficacy of the given therapeutic interventions. At the centre of this puzzle lies ACE2 that works as a receptor for the SARS-CoV-2, and functional expression of which is also needed to minimize vasoconstriction otherwise would lead to high blood pressure. Furthermore, SARS-CoV-2 infection seems to reduce the functional expression of ACE2. Given these circumstances, it might be advisable to consider a treatment plan for COVID-19 patients with CVD in an approach that would neither aggravate the vasodeleterious arm of the renin-angiotensinogen-aldosterone system (RAAS) nor compromise the vasoprotective arm of RAAS but is effective to minimize or if possible, inhibit the viral replication. Given the immune modulatory role of Zn in both CVD and COVID-19 pathogenesis, zinc supplement to the selective treatment plan for CVD and COVID-19 comorbid conditions, to be decided by the clinicians depending on the cardiovascular conditions of the patients, might greatly improve the therapeutic outcome. Notably, ACE2 is a zinc metalloenzyme and zinc is also known to inhibit viral replication.


Subject(s)
COVID-19 , Cardiovascular Diseases , Angiotensin-Converting Enzyme 2 , Cardiovascular Diseases/epidemiology , Comorbidity , Humans , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System , SARS-CoV-2 , Zinc
14.
Genes (Basel) ; 12(10)2021 10 01.
Article in English | MEDLINE | ID: covidwho-1444159

ABSTRACT

The renin-angiotensin-aldosterone system (RAAS) appears to play an important role in SARS-CoV-2 infection. Polymorphisms within the genes that control this enzymatic system are candidates for elucidating the pathogenesis of COVID-19, since COVID-19 is not only a pulmonary disease but also affects many organs and systems throughout the body in multiple ways. Most striking is the fact that ACE2, one of the major components of the RAAS, is a prerequisite for SARS-COV-2 infection. Recently, we and other groups reported an association between a polymorphism of the ACE1 gene (a homolog of ACE2) and the phenotypic expression of COVID-19, particularly in its severity. The ethnic difference in ACE1 insertion (I)/deletion (D) polymorphism seems to explain the apparent difference in mortality between the West and East Asia. The purpose of this review was to further evaluate the evidence linking ACE1 polymorphisms to COVID-19. We searched the Medline database (2019-2021) for reference citations of relevant articles and selected studies on the clinical outcome of COVID-19 related to ACE1 I/D polymorphism. Although the numbers of patients are not large enough yet, most available evidence supports the notion that the DD genotype adversely influences COVID-19 symptoms. Surprisingly, small studies conducted in several countries yielded opposite results, suggesting that the ACE1 II genotype is a risk factor. This contradictory result may be the case in certain geographic areas, especially in subgroups of patients. It may also be due to interactions with other genes or to yet unexplained biochemical mechanisms. According to our hypothesis, such candidates are genes that are functionally involved in the pathophysiology of COVID-19, can act in concert with the ACE1 DD genotype, and that show differences in their frequency between the West and East Asia. For this, we conducted research focusing on Alu-related genes. The current study on the ACE1 genotype will provide potentially new clues to the pathogenesis, treatment, and diagnosis of SARS-CoV-2 infections.


Subject(s)
COVID-19 , Gene Expression Regulation, Viral , Genotype , INDEL Mutation , Peptidyl-Dipeptidase A , Polymorphism, Genetic , SARS-CoV-2/metabolism , COVID-19/genetics , COVID-19/metabolism , Humans , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Risk Factors
15.
PLoS One ; 16(9): e0257905, 2021.
Article in English | MEDLINE | ID: covidwho-1440993

ABSTRACT

SARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for an invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS-CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make the RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in a reduced dissociation rate of SARS-CoV-2 from human receptor protein compared to SARS-CoV. The phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study adds more insight into the critical dynamics of the key residues at the virus spike and human receptor binding interface and potentially aids the development of diagnostics and therapeutics to combat the pandemic efficiently.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , SARS-CoV-2/genetics , Angiotensin-Converting Enzyme 2/genetics , Binding Sites , COVID-19/genetics , Humans , Models, Theoretical , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/metabolism , Protein Binding , Protein Domains , Protein Interaction Domains and Motifs/genetics , Protein Interaction Domains and Motifs/physiology , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
16.
J Med Virol ; 93(10): 5947-5952, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1432432

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease, and the reason behind the currently ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme (ACE2) has been recognized as the specific receptor of the SARS-CoV-2 virus. Although the possible effect of ACE2 gene polymorphism remains unknown, human ACE2 receptor expression influences SARS-CoV-2 susceptibility and COVID-19 disease outcome. In this study, we aimed to investigate the relationship between ACE gene I/D polymorphism, ACE2 receptor gene polymorphism, and COVID-19 severity. ACE gene insertion/deletion (I/D) polymorphism and ACE2 receptor gene rs2106809 and rs2285666 polymorphisms were determined using polymerase chain reaction (PCR) and PCR-based restriction fragment length polymorphism methods, respectively, in 155 COVID-19 patients who were divided into three groups (mild, moderate, and severe) according to clinical symptoms. However, the distribution of genotype and allele frequencies of ACE gene I/D, ACE2 receptor gene rs2106809, and rs2285666 polymorphisms were not statistically significant in all groups. In conclusion, in the study population, ACE gene I/D, ACE2 receptor gene rs2106809, and rs2285666 polymorphisms were not associated with the severity of COVID-19 infection. Although ACE2 receptor gene expression may affect the susceptibility to COVID-19, there is no existing evidence that the ACE or ACE2 gene polymorphisms are directly associated with COVID-19 severity. Interindividual differences in COVID-19 severity might be related to epigenetic mechanisms of ACE2 receptor gene expression or variations in other genes suggested to play a critical role in COVID-19 pathogenesis such as pro-inflammatory cytokines and coagulation indicators.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Peptidyl-Dipeptidase A/genetics , Adult , Aged , COVID-19/diagnosis , Gene Frequency , Genetic Association Studies , Genotype , Humans , Middle Aged , Negative Results , Polymorphism, Single Nucleotide , SARS-CoV-2 , Severity of Illness Index
17.
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
18.
Clin Lab ; 67(9)2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1431125

ABSTRACT

BACKGROUND: Chest CT is important for the diagnosis of Corona Virus Disease 2019, which is caused by SARS-CoV-2 via the receptor angiotensin-converting enzyme 2. This study aimed to present special chest CT changes in the detection and management of COVID-19. METHODS: From February 20 to March 6, 2020, clinical data and chest CT of patients with COVID-19 being treated by the Hubei Medical Team were retrospectively analyzed with a time-interval of 2 weeks. In addition, the expressions of ACE2 in different parts of the respiratory system were detected by immunohistochemical staining to explain the special chest CT features of COVID-19 by ACE2 expression. RESULTS: Of 58 patients, the main respiratory manifestations were fever and cough. Spherical or patchy GGO was the initial CT manifestation of COVID-19 pneumonia. CT findings manifested as rapid evolution from focal unilateral to diffuse bilateral ground-glass opacities (GGO) that progressed to or co-existed with consolidations in chest CT scans. Lung consolidation increased as the disease progressed, accounting for 63.2%, 76.3%, and 87.5% in group 1 (disease course with 0 - 2 weeks), group 2 (2 - 4 weeks), and group 3 (> 4 weeks). Fibrous lesions (72.3%), high density vascular shadow (69.2%), reticular pattern (63.1%), and subpleural parallel sign (61.5%) were common signs of chest CT of COVID-19. IHC results showed that ACE2-expression in the pulmonary alveoli was significantly higher than that in the bronchial mucosa and pleura (p < 0.001). CONCLUSIONS: The special change of CT features in the lung of COVID-19 pneumonia patients have a connection with ACE2 expression patterns in the respiratory system.


Subject(s)
COVID-19 , Peptidyl-Dipeptidase A , Humans , Lung/diagnostic imaging , Retrospective Studies , SARS-CoV-2 , Tomography, X-Ray Computed
19.
J Renin Angiotensin Aldosterone Syst ; 2021: 5509280, 2021.
Article in English | MEDLINE | ID: covidwho-1430254

ABSTRACT

Introduction: The coronavirus disease 2019 (COVID-19), that is caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), has spread rapidly worldwide since December 2019. The SARS-CoV-2 virus has a great affinity for the angiotensin-converting enzyme-2 (ACE-2) receptor, which is an essential element of the renin-angiotensin system (RAS). This study is aimed at assessing the impact of the angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphisms, on the susceptibility and clinical outcomes of the COVID-19 immunoinflammatory syndrome. Patients and Methods. A total of 112 patients diagnosed with COVID-19 between 1 and 15 May 2020 were enrolled in the study. ACE gene allele frequencies were compared to the previously reported Turkish population comprised of 300 people. Results: The most common genotype in the patients and control group was DI with 53% and II with 42%, respectively. The difference in the presence of the D allele between the patient and control groups was statistically significant (67% vs. 42%, respectively, p < 0.0001). Severe pneumonia was observed more in patients with DI allele (31%) than DD (8%) and II (0%) (p = 0.021). The mortality rate, time to defervescence, and the hospitalization duration were not different between the genotype groups. Conclusion: Genotype DI of ACE I/D polymorphism is associated with the infectious rate particularly severe pneumonia in this study conducted in the Turkish population. Therefore, ACE D/I polymorphism could affect the clinical course of COVID-19.


Subject(s)
COVID-19/genetics , Peptidyl-Dipeptidase A/genetics , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Gene Frequency , Genetic Association Studies , Humans , INDEL Mutation , Male , Middle Aged , Polymorphism, Genetic , Renin-Angiotensin System , Young Adult
20.
BMJ Case Rep ; 14(9)2021 Sep 20.
Article in English | MEDLINE | ID: covidwho-1430178

ABSTRACT

We describe a patient who developed acute bilateral corneal decompensation following COVID-19 pneumonia and prolonged intensive care unit ventilation. SARS-CoV-2 uses human ACE2 as the receptor for entry with subsequent downregulation of ACE2. ACE2 receptors are found in human ocular surface cells including cornea. Mouse models of ACE2 deficiency result in corneal haze, oedema and ocular surface inflammation due to upregulation of the inflammatory cascades. We therefore hypothesise that the cause of this patient's corneal decompensation was viral endotheliitis due to direct infection by the SARS-CoV-2 virus.


Subject(s)
COVID-19 , Animals , Cornea , Endothelium, Corneal , Humans , Inflammation , Mice , Peptidyl-Dipeptidase A , SARS-CoV-2
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