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1.
Int J Mol Sci ; 23(7)2022 Apr 02.
Article in English | MEDLINE | ID: covidwho-1785742

ABSTRACT

The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis.


Subject(s)
Antibodies , Receptor, Angiotensin, Type 1 , Alanine , Angiotensin II , Antibodies/pharmacology , Cell Proliferation , HEK293 Cells , Humans , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism
2.
Int J Mol Sci ; 23(5)2022 Feb 22.
Article in English | MEDLINE | ID: covidwho-1736940

ABSTRACT

Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.


Subject(s)
Angiotensin II/metabolism , Hypertension/metabolism , Receptor, Angiotensin, Type 1/metabolism , Angiotensin II/genetics , Animals , Blood Pressure , Disease Models, Animal , Gain of Function Mutation , Humans , Hypertension/genetics , Loss of Function Mutation , Mice , Receptor, Angiotensin, Type 1/genetics , Sodium-Hydrogen Exchanger 3/metabolism
3.
PLoS One ; 17(2): e0263140, 2022.
Article in English | MEDLINE | ID: covidwho-1666767

ABSTRACT

BACKGROUND: Infection by the SARS-Cov-2 virus produces in humans a disease of highly variable and unpredictable severity. The presence of frequent genetic single nucleotide polymorphisms (SNPs) in the population might lead to a greater susceptibility to infection or an exaggerated inflammatory response. SARS-CoV-2 requires the presence of the ACE2 protein to enter in the cell and ACE2 is a regulator of the renin-angiotensin system. Accordingly, we studied the associations between 8 SNPs from AGTR1, ACE2 and ACE genes and the severity of the disease produced by the SARS-Cov-2 virus. METHODS: 318 (aged 59.6±17.3 years, males 62.6%) COVID-19 patients were grouped based on the severity of symptoms: Outpatients (n = 104, 32.7%), hospitalized on the wards (n = 73, 23.0%), Intensive Care Unit (ICU) (n = 84, 26.4%) and deceased (n = 57, 17.9%). Comorbidity data (diabetes, hypertension, obesity, lung disease and cancer) were collected for adjustment. Genotype distribution of 8 selected SNPs among the severity groups was analyzed. RESULTS: Four SNPs in ACE2 were associated with the severity of disease. While rs2074192 andrs1978124showed a protector effectassuming an overdominant model of inheritance (G/A vs. GG-AA, OR = 0.32, 95%CI = 0.12-0.82; p = 0.016 and A/G vs. AA-GG, OR = 0.37, 95%CI: 0.14-0.96; p = 0.038, respectively); the SNPs rs2106809 and rs2285666were associated with an increased risk of being hospitalized and a severity course of the disease with recessive models of inheritance (C/C vs. T/C-T/T, OR = 11.41, 95% CI: 1.12-115.91; p = 0.012) and (A/A vs. GG-G/A, OR = 12.61, 95% CI: 1.26-125.87; p = 0.0081). As expected, an older age (OR = 1.47), male gender (OR = 1.98) and comorbidities (OR = 2.52) increased the risk of being admitted to ICU or death vs more benign outpatient course. Multivariable analysis demonstrated the role of the certain genotypes (ACE2) with the severity of COVID-19 (OR: 0.31, OR 0.37 for rs2074192 and rs1978124, and OR = 2.67, OR = 2.70 for rs2106809 and rs2285666, respectively). Hardy-Weinberg equilibrium in hospitalized group for I/D SNP in ACE was not showed (p<0.05), which might be due to the association with the disease. No association between COVID-19 disease and the different AGTR1 SNPs was evidenced on multivariable, nevertheless the A/A genotype for rs5183 showed an higher hospitalization risk in patients with comorbidities. CONCLUSIONS: Different genetic variants in ACE2 were associated with a severe clinical course and death groups of patients with COVID-19. ACE2 common SNPs in the population might modulate severity of COVID-19 infection independently of other known markers like gender, age and comorbidities.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/pathology , Peptidyl-Dipeptidase A/genetics , Polymorphism, Single Nucleotide , Receptor, Angiotensin, Type 1/genetics , SARS-CoV-2/genetics , Severity of Illness Index , Aged , COVID-19/genetics , COVID-19/virology , Female , Genotype , Humans , Male , Middle Aged
4.
Infect Genet Evol ; 98: 105227, 2022 03.
Article in English | MEDLINE | ID: covidwho-1648267

ABSTRACT

INTRODUCTION: The severity of SARS-CoV-2 induced coronavirus disease 19 (COVID-19) depends on the presence of risk factors and the hosts' gene variability. There are preliminary results that gene polymorphisms of the renin-angiotensin system can influence the susceptibility to and mortality from COVID-19. Angiotensin II type 1 receptor (AT1R) might be a gene candidate that exerts such influence. The aim of this study was to elaborate on the association between A1166C at1r polymorphic variants and the susceptibility to and severity of COVID-19 in the Ukrainian population. METHODS: The study population consisted of the Ukrainian population (Poltava region) with COVID-19, divided into three clinical groups in accordance with oxygen requirement: patients without oxygen therapy (n = 110), with non-invasive (n = 136) and invasive (n = 36) oxygen therapy. The A1166C polymorphism of the at1r was determined by polymerase chain reaction with subsequent restrictase analysis. In an attempt to better explain the role of the A1166C at1r polymorphism we compared its association with COVID-19, essential hypertension (n = 79), renoparenchimal hypertension (n = 30) and dyscirculatory encephalopathy (n = 112). The data for this comparison were obtained by meta-analysis. RESULTS: We observed significant differences in the frequency of AA, AC and CC genotypes in the groups of COVID-19 patients with non-invasive and invasive oxygen therapy in comparison with control subjects as well as in the frequency of combined AC + CC genotype between the groups of COVID-19 patients with any types of oxygen therapy and patients without oxygen therapy. The frequency of the 1166C allele was higher in COVID-19 patients with invasive oxygen therapy (OR = 2.06; CI (1.20-3.53); p = 0.013). We obtained important results indicating that there were no differences between the frequency of at1r polymorphisms in patients with cardiovascular disease and severe COVID-19 with invasive oxygen therapy as well as those who died due to COVID-19. CONCLUSION: Our study indicated the presence of an association between the A1166C at1r polymorphisms and the severity of COVID-19 in the Ukrainian population. It seems that in carriers of 1166C at1r, the severity of COVID-19 and oxygen dependency is higher as compared to the A allele carriers, possibly, due to cardiovascular disorders.


Subject(s)
COVID-19/genetics , COVID-19/therapy , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Receptor, Angiotensin, Type 1/genetics , SARS-CoV-2/genetics , Severity of Illness Index , Adult , Alleles , COVID-19/epidemiology , Female , Genotype , Humans , Male , Middle Aged , Respiration, Artificial/methods , Respiration, Artificial/statistics & numerical data , Risk Factors , Ukraine/epidemiology
5.
Epigenomics ; 14(3): 153-162, 2022 02.
Article in English | MEDLINE | ID: covidwho-1622527

ABSTRACT

Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.


Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.


Subject(s)
COVID-19/genetics , Dioxygenases/genetics , Epigenesis, Genetic , Histone Demethylases/genetics , Histones/genetics , Nuclear Proteins/genetics , Protein Processing, Post-Translational , Smoking/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/virology , Cathepsin D/genetics , Cathepsin D/metabolism , Cathepsin L/genetics , Cathepsin L/metabolism , Dioxygenases/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Methylation , Neuropilin-1/genetics , Neuropilin-1/metabolism , Neuropilin-2/genetics , Neuropilin-2/metabolism , Nuclear Proteins/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E/metabolism , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Smoking/metabolism , Smoking/pathology , Virus Internalization
6.
Sci Rep ; 11(1): 24397, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1585779

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is an important factor in coronavirus disease (COVID-19) interactions. Losartan (LOS) belongs to the angiotensin receptor blocker (ARB) family. Additionally, the protective role of ACE2 restored by LOS has been suggested and clinically examined in the treatment of COVID-19 patients. Furthermore, clinical trials with LOS have been conducted. However, the mechanism through which LOS enhances ACE2 expression remains unclear. In addition, the response of ACE2 to LOS differs among patients. Our LOS-treated patient data revealed a correlated mechanism of ACE2 with components of the renin-angiotensinogen system. We observed a significant positive regulation of MAS1 and ACE2 expression. In the context of LOS treatment of COVID-19, ACE2 expression could depend on LOS regulated MAS1. Thus, MAS1 expression could predict the COVID-19 treatment response of LOS.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Losartan/pharmacology , Renin-Angiotensin System/drug effects , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2/genetics , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Databases, Factual , Humans , Losartan/therapeutic use , /metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , SARS-CoV-2/isolation & purification , Up-Regulation/drug effects
7.
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
8.
PLoS One ; 16(9): e0257016, 2021.
Article in English | MEDLINE | ID: covidwho-1388955

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
9.
Adipocyte ; 10(1): 408-411, 2021 12.
Article in English | MEDLINE | ID: covidwho-1360282

ABSTRACT

Angiotensin converting enzyme-2 (ACE2) is the cell-surface receptor enabling cellular entry of SARS-CoV-2. ACE2 is highly expressed in adipose tissue (AT), rendering AT a potential SARS-CoV-2 reservoir contributing to massive viral spread in COVID-19 patients with obesity. Although rodent and cell studies suggest that the polyphenol resveratrol alters ACE2, human studies are lacking. Here, we investigated the effects of 30-days resveratrol supplementation on RAS components in AT and skeletal muscle in men with obesity in a placebo-controlled cross-over study. Resveratrol markedly decreased ACE2 (~40%) and leptin (~30%), but did neither alter angiotensinogen, ACE and AT1R expression in AT nor skeletal muscle RAS components. These findings demonstrate that resveratrol supplementation reduces ACE2 in AT, which might dampen SARS-CoV-2 spread in COVID-19.


Subject(s)
Adipose Tissue/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Resveratrol/administration & dosage , Adipose Tissue/cytology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/pathology , COVID-19/virology , Cross-Over Studies , Dietary Supplements , Double-Blind Method , Down-Regulation/drug effects , Humans , Leptin/genetics , Leptin/metabolism , Male , Middle Aged , Obesity/drug therapy , Obesity/pathology , Placebo Effect , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Resveratrol/pharmacology , SARS-CoV-2/isolation & purification
10.
Biomed Pharmacother ; 141: 111722, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1252499

ABSTRACT

Coronavirus disease 2019 is associated with clinical symptoms including severe inflammatory syndrome and a higher expression of angiotensin II. As a pro-inflammatory mediator, the physiologic effects of angiotensin II are mediated by a G-protein coupled receptor, termed AT1R. Following binding, AT1R initiates the process of signal desensitization necessary to maintain cellular homeostasis. At the cellular level, this function occurs via the G protein-dependent signaling and the phosphorylation. We describe amino acids similarities between SARS COV-2 nonstructural protein (NSP8) which is associated with intracellular membranes and AT1R key sites. Since abnormal activation of AT1R receptor leads to a number of physiological disorders, we hypothesize that SARS COV-2 might further interfere with the angiotensin II receptor functions.


Subject(s)
Coronavirus RNA-Dependent RNA Polymerase/genetics , Oligopeptides/genetics , Receptor, Angiotensin, Type 1/genetics , SARS-CoV-2/genetics , Viral Nonstructural Proteins/genetics , Amino Acid Sequence , COVID-19/genetics , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Humans , Oligopeptides/chemistry , Receptor, Angiotensin, Type 1/chemistry , SARS-CoV-2/chemistry , Viral Nonstructural Proteins/chemistry
11.
Respir Res ; 22(1): 164, 2021 May 29.
Article in English | MEDLINE | ID: covidwho-1247590

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. METHODS: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. RESULTS: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively). CONCLUSION: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.


Subject(s)
COVID-19/genetics , Lung/metabolism , Pulmonary Disease, Chronic Obstructive/genetics , Transcriptome , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Basigin/genetics , Basigin/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/physiopathology , Case-Control Studies , Female , Forced Expiratory Volume , Gene Expression Regulation , Humans , Lung/physiopathology , Male , Middle Aged , Prognosis , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/physiopathology , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/genetics , Receptor, Angiotensin, Type 2/metabolism , Vital Capacity
12.
Bioessays ; 43(3): e2000112, 2021 03.
Article in English | MEDLINE | ID: covidwho-985954

ABSTRACT

This renin-angiotensin system (RAS) interpretation is focused on differences in tissue dependence on RAS and on the topological hierarchy that allows mediators to act only on downstream tissues. Dependence of tissues on RAS: Tested by expectation maximization clustering of the RNA human tissue expression (https://biogps.org/). ACE and vasoconstrictive AT1R clustered with the prorenin receptor. ACE2 and dilatory MAS1 clustered with nine RAS-related genes, highly expressed in: Liver; Cardiac_Myocytes; Skeletal_Muscle; Uterus; Kidney; Lung; Small_Intestine; Smooth_Muscle. RAS and stress accumulation: While prorenin is active after binding to its receptor, binding of soluble renin increases its enzymatic activity several times. Increased renin secretion multiplies the overall capacity for producing Ang I, leading to hypertension and increased vascular resistance. Coronavirus infection and comorbidities: Cardiorespiratory failure during infection is linked to the previously altered RAS role in lungs and myocardium. Reduced vasodilation by ACE2 lead to vasoconstriction and suboptimal tissue perfusion patterns. Also see the video abstract here https://www.youtube.com/watch?v=Jf0Iped-Mws.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Hypertension/genetics , Renin-Angiotensin System/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Aged , Angiotensin I/genetics , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/mortality , COVID-19/virology , Gene Expression Regulation , Humans , Hypertension/metabolism , Hypertension/mortality , Hypertension/virology , Lung/metabolism , Lung/pathology , Lung/virology , Myocardium/metabolism , Myocardium/pathology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptor, Angiotensin, Type 2/genetics , Receptor, Angiotensin, Type 2/metabolism , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Renin/genetics , Renin/metabolism , Signal Transduction , Survival Analysis
13.
J Ovarian Res ; 13(1): 79, 2020 Jul 19.
Article in English | MEDLINE | ID: covidwho-657841

ABSTRACT

The outbreak and continued spread of the novel coronavirus disease 2019 (COVID-19) is a preeminent global health threat that has resulted in the infection of over 11.5 million people worldwide. In addition, the pandemic has claimed the lives of over 530,000 people worldwide. Age and the presence of underlying comorbid conditions have been found to be key determinants of patient mortality. One such comorbidity is the presence of an oncological malignancy, with cancer patients exhibiting an approximate two-fold increase in mortality rate. Due to a lack of data, no consensus has been reached about the best practices for the diagnosis and treatment of cancer patients. Interestingly, two independent research groups have discovered that Withaferin A (WFA), a steroidal lactone with anti-inflammatory and anti-tumorigenic properties, may bind to the viral spike (S-) protein of SARS-CoV-2. Further, preliminary data from our research group has demonstrated that WFA does not alter expression of ACE2 in the lungs of tumor-bearing female mice. Downregulation of ACE2 has recently been demonstrated to increase the severity of COVID-19. Therefore, WFA demonstrates real potential as a therapeutic agent to treat or prevent the spread of COVID-19 due to the reported interference in viral S-protein to host receptor binding and its lack of effect on ACE2 expression in the lungs.


Subject(s)
Angiotensin II/drug effects , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral/drug therapy , Receptor, Angiotensin, Type 1/drug effects , Withanolides/pharmacology , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/metabolism , COVID-19 , Cachexia/metabolism , Female , Humans , Mice , Ovarian Neoplasms/drug therapy , Pandemics , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Receptor, Angiotensin, Type 1/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Xenograft Model Antitumor Assays
14.
Rev Med Virol ; 30(5): e2119, 2020 09.
Article in English | MEDLINE | ID: covidwho-613704

ABSTRACT

The novel coronavirus disease 2019 (COVID-19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point into cells for SARS-CoV-2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat-soluble-vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang-(1-7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang-(1-7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down-regulation with vitamin D in SARS-CoV-2 infection is a potential therapeutic approach to combat COVID-19 and induced ARDS.


Subject(s)
Acute Lung Injury/prevention & control , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/drug therapy , Receptors, Virus/genetics , Vitamin D/therapeutic use , Acute Lung Injury/pathology , Acute Lung Injury/virology , Angiotensin I/genetics , Angiotensin I/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gene Expression Regulation/drug effects , Humans , Pandemics , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/metabolism , Renin-Angiotensin System/drug effects , SARS-CoV-2 , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
15.
Int Arch Allergy Immunol ; 181(6): 467-475, 2020.
Article in English | MEDLINE | ID: covidwho-235502

ABSTRACT

After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1-7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.


Subject(s)
Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Azetidines/therapeutic use , Coronavirus Infections/drug therapy , Janus Kinases/genetics , Methotrexate/therapeutic use , Pandemics , Peptide Fragments/therapeutic use , Pneumonia, Viral/drug therapy , Sulfonamides/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Progression , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/immunology , Molecular Targeted Therapy/methods , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Purines , Pyrazoles , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/immunology , SARS-CoV-2 , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/genetics , STAT Transcription Factors/immunology , Signal Transduction/genetics , Signal Transduction/immunology
16.
J Med Virol ; 92(7): 726-730, 2020 07.
Article in English | MEDLINE | ID: covidwho-17559

ABSTRACT

This article reviews the correlation between angiotensin-converting enzyme 2 (ACE2) and severe risk factors for coronavirus disease 2019 (COVID-19) and the possible mechanisms. ACE2 is a crucial component of the renin-angiotensin system (RAS). The classical RAS ACE-Ang II-AT1R regulatory axis and the ACE2-Ang 1-7-MasR counter-regulatory axis play an essential role in maintaining homeostasis in humans. ACE2 is widely distributed in the heart, kidneys, lungs, and testes. ACE2 antagonizes the activation of the classical RAS system and protects against organ damage, protecting against hypertension, diabetes, and cardiovascular disease. Similar to SARS-CoV, SARS-CoV-2 also uses the ACE2 receptor to invade human alveolar epithelial cells. Acute respiratory distress syndrome (ARDS) is a clinical high-mortality disease, and ACE2 has a protective effect on this type of acute lung injury. Current research shows that the poor prognosis of patients with COVID-19 is related to factors such as sex (male), age (>60 years), underlying diseases (hypertension, diabetes, and cardiovascular disease), secondary ARDS, and other relevant factors. Because of these protective effects of ACE2 on chronic underlying diseases and ARDS, the development of spike protein-based vaccine and drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID-19 in the future.


Subject(s)
Betacoronavirus/pathogenicity , Cardiovascular Diseases/genetics , Coronavirus Infections/genetics , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Spike Glycoprotein, Coronavirus/genetics , Age Factors , Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Cardiovascular Diseases/complications , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Peptide Fragments/therapeutic use , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Prognosis , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2 , Sex Factors , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism
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