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1.
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
2.
Int J Med Sci ; 19(2): 402-415, 2022.
Article in English | MEDLINE | ID: covidwho-1662815

ABSTRACT

Hypertension, diabetes mellitus, and coronary artery disease are common comorbidities and dangerous factors for infection and serious COVID-19. Polymorphisms in genes associated with comorbidities may help observe susceptibility and disease severity variation. However, specific genetic factors and the extent to which they can explain variation in susceptibility of severity are unclear. Therefore, we evaluated candidate genes associated with COVID-19 and hypertension, diabetes mellitus, and coronary artery disease. In particular, we performed searches against OMIM, NCBI, and other databases, protein-protein interaction network construction, and GO and KEGG pathway enrichment analyses. Results showed that the associated overlapping genes were TLR4, NLRP3, MBL2, IL6, IL1RN, IL1B, CX3CR1, CCR5, AGT, ACE, and F2. GO and KEGG analyses yielded 302 GO terms (q < 0.05) and 29 signaling pathways (q < 0.05), respectively, mainly including coronavirus disease-COVID-19 and cytokine-cytokine receptor interaction. IL6 and AGT were central in the PPI, with 8 and 5 connections, respectively. In this study, we identified 11 genes associated with both COVID-19 and three comorbidities that may contribute to infection and disease severity. The key genes IL6 and AGT are involved in regulating immune response, cytokine activity, and viral infection. Therefore, RAAS inhibitors, AGT antisense nucleotides, cytokine inhibitors, vitamin D, fenofibrate, and vaccines regulating non-immune and immune factors could be potential strategies to prevent and cure COVID-19. The study provides a basis for further investigation of genes and pathways with predictive value for the risk of infection and prognosis and could help guide drug and vaccine development to improve treatment efficacy and the development of personalised treatments, especially for COVID-19 individuals with common comorbidities.


Subject(s)
COVID-19/genetics , COVID-19/epidemiology , Comorbidity , Coronary Artery Disease/complications , Coronary Artery Disease/epidemiology , Coronary Artery Disease/genetics , Diabetes Complications/epidemiology , Diabetes Complications/genetics , Humans , Hypertension/complications , Hypertension/epidemiology , Hypertension/genetics , Mutation , Protein Interaction Maps
3.
Front Endocrinol (Lausanne) ; 12: 688071, 2021.
Article in English | MEDLINE | ID: covidwho-1399132

ABSTRACT

Coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to scale and threaten human health and public safety. It is essential to identify those risk factors that lead to a poor prognosis of the disease. A predisposing host genetic background could be one of these factors that explain the interindividual variability to COVID-19 severity. Thus, we have studied whether the rs4341 and rs4343 polymorphisms of the angiotensin converting enzyme (ACE) gene, key regulator of the renin-aldosterone-angiotensin system (RAAS), could explain the different outcomes of 128 COVID-19 patients with diverse degree of severity (33 asymptomatic or mildly symptomatic, 66 hospitalized in the general ward, and 29 admitted to the ICU). We found that G allele of rs4341 and rs4343 was associated with severe COVID-19 in hypertensive patients, independently of gender (p<0.05). G-carrier genotypes of both polymorphisms were also associated with higher mortality (p< 0.05) and higher severity of COVID-19 in dyslipidemic (p<0.05) and type 2 diabetic patients (p< 0.01). The association of G alleles with disease severity was adjusted for age, sex, BMI and number of comorbidities, suggesting that both the metabolic comorbidities and the G allele act synergistically on COVID-19 outcome. Although we did not find a direct association between serum ACE levels and COVID-19 severity, we found higher levels of ACE in the serum of patients with the GG genotype of rs4341 and rs4343 (p<0.05), what could explain the higher susceptibility to develop severe forms of the disease in patients with the GG genotype, in addition to hypertension and dyslipidemia. In conclusion, our preliminary study suggests that the G-containing genotypes of rs4341 and rs4343 confer an additional risk of adverse COVID-19 prognosis. Thus, rs4341 and rs4343 polymorphisms of ACE could be predictive markers of severity of COVID-19 in those patients with hypertension, dyslipidemia or diabetes. The knowledge of these genetic data could contribute to precision management of SARS-CoV-2 infected patients when admitted to hospital.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , Dyslipidemias/genetics , Genetic Variation/genetics , Hypertension/genetics , Peptidyl-Dipeptidase A/genetics , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Dyslipidemias/diagnosis , Dyslipidemias/epidemiology , Female , Hospitalization/trends , Humans , Hypertension/diagnosis , Hypertension/epidemiology , Male , Middle Aged , Pilot Projects , Risk Factors , Severity of Illness Index , Spain/epidemiology
4.
Pregnancy Hypertens ; 26: 17-23, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1364411

ABSTRACT

AIMS: The aim of this study was to apply the Mendelian randomization (MR) design to explore the potential causal association between COVID-19 and the risk of hypertension disorders in pregnancy. METHODS: Our primary genetic instrument comprised 8 single-nucleotide polymorphisms (SNPs) associated with COVID-19 at genome-wide significance. Data on the associations between the SNPs and the risk of hypertension disorders in pregnancy were obtained from study based on a very large cohort of European population. The random-effects inverse-variance weighted method was conducted for the main analyses, with a complementary analysis of the weighted median and MR-Egger approaches. RESULTS: Using IVW, we found that genetically predicted COVID-19 was significantly positively associated with hypertension disorders in pregnancy, with an odds ratio (OR) of 1.111 [95% confidence interval (CI) 1.042-1.184; P = 0.001]. Weighted median regression also showed directionally similar estimates [OR 1.098 (95% CI, 1.013-1.190), P = 0.023]. Both funnel plots and MR-Egger intercepts suggest no directional pleiotropic effects observed. CONCLUSIONS: Our findings provide direct evidence that there is a shared genetic predisposition so that patients infected with COVID-19 may be causally associated with increased risk of hypertension disorders in pregnancy.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , Hypertension/etiology , Mendelian Randomization Analysis/methods , Polymorphism, Single Nucleotide , Risk Assessment/methods , SARS-CoV-2 , COVID-19/complications , COVID-19/epidemiology , Female , Global Health , Humans , Hypertension/epidemiology , Hypertension/genetics , Incidence , Pregnancy , Risk Factors
5.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1254437

ABSTRACT

Despite the association of prevalent health conditions with coronavirus disease 2019 (COVID-19) severity, the disease-modifying biomolecules and their pathogenetic mechanisms remain unclear. This study aimed to understand the influences of COVID-19 on different comorbidities and vice versa through network-based gene expression analyses. Using the shared dysregulated genes, we identified key genetic determinants and signaling pathways that may involve in their shared pathogenesis. The COVID-19 showed significant upregulation of 93 genes and downregulation of 15 genes. Interestingly, it shares 28, 17, 6 and 7 genes with diabetes mellitus (DM), lung cancer (LC), myocardial infarction and hypertension, respectively. Importantly, COVID-19 shared three upregulated genes (i.e. MX2, IRF7 and ADAM8) with DM and LC. Conversely, downregulation of two genes (i.e. PPARGC1A and METTL7A) was found in COVID-19 and LC. Besides, most of the shared pathways were related to inflammatory responses. Furthermore, we identified six potential biomarkers and several important regulatory factors, e.g. transcription factors and microRNAs, while notable drug candidates included captopril, rilonacept and canakinumab. Moreover, prognostic analysis suggests concomitant COVID-19 may result in poor outcome of LC patients. This study provides the molecular basis and routes of the COVID-19 progression due to comorbidities. We believe these findings might be useful to further understand the intricate association of these diseases as well as for the therapeutic development.


Subject(s)
COVID-19/genetics , Diabetes Mellitus/genetics , Hypertension/genetics , Lung Neoplasms/genetics , Myocardial Infarction/genetics , Transcriptome/genetics , ADAM Proteins , COVID-19/virology , Computational Biology , Humans , Interferon Regulatory Factor-7 , Lung Neoplasms/pathology , Membrane Proteins , Myxovirus Resistance Proteins/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Transcription Factors/genetics
6.
Clin Nutr ESPEN ; 44: 475-478, 2021 08.
Article in English | MEDLINE | ID: covidwho-1242904

ABSTRACT

BACKGROUND & AIMS: Obesity is associated with low grade systemic inflammation and insulin resistance. Although metabolic and immunological changes may contribute to the increased risk for COVID-19 mortality in obese, little is known about the impact of obesity in the lungs of patients with COVID-19. METHODS: We analyzed gene expression profiles of autopsy lungs of a cohort of 14 COVID-19 patients and 4 control individuals. Patients were divided into 3 groups according to their comorbidities: hypertension, type 2 diabetes (T2D) and obesity. We then identified the molecular alterations associated with these comorbidities in COVID-19 patients. RESULTS: Patients with only hypertension showed higher levels of inflammatory genes and B-cell related genes when compared to those with T2D and obesity. However, the levels of IFN-gamma, IL22, and CD274 (a ligand that binds to receptor PD1) were higher in COVID-19 patients with T2D and obesity. Several metabolic- and immune-associated genes such as G6PD, LCK and IL10 were significantly induced in the lungs of the obese group. CONCLUSION: Our findings suggest that SARS-CoV-2 infection in the lungs may exacerbate the immune response and chronic condition in obese COVID-19 patients.


Subject(s)
COVID-19/complications , COVID-19/genetics , Gene Expression/genetics , Lung/immunology , Obesity/complications , Obesity/genetics , Autopsy , COVID-19/immunology , Cohort Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/immunology , Obesity/immunology , SARS-CoV-2
7.
Vascul Pharmacol ; 140: 106861, 2021 10.
Article in English | MEDLINE | ID: covidwho-1180098

ABSTRACT

The virus responsible for the coronavirus disease of 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidences suggest that COVID-19 could trigger cardiovascular complications in apparently healthy patients. Coronaviruses are enveloped positive-strand RNA viruses acting as a pathogen-associated molecular pattern (PAMP)/ danger-associated molecular patterns (DAMP). Interestingly, Toll-like receptor (TLR) 3 recognize both PAMPs DAMPs and is activated by viral double-stranded RNA (dsRNA) leading to activation of TIR receptor domain-containing adaptor inducing IFN-ß (TRIF) dependent pathway. New evidence has shown a link between virus dsRNA and increased BP. Hence, we hypothesize that COVID-19 infection may be over activating the TLR3 through dsRNA, evoking further damage to the patients, leading to vascular inflammation and increased blood pressure, favoring the development of several cardiovascular complications, including hypertension.


Subject(s)
COVID-19/genetics , COVID-19/pathology , Hypertension/genetics , RNA, Double-Stranded/genetics , Toll-Like Receptor 3/genetics , Animals , Humans , Hypertension/pathology , Hypertension/virology , Mice , SARS-CoV-2/pathogenicity , Signal Transduction/genetics
8.
Int J Mol Sci ; 22(4)2021 Feb 08.
Article in English | MEDLINE | ID: covidwho-1069831

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) have a wide variety of clinical outcomes ranging from asymptomatic to severe respiratory syndrome that can progress to life-threatening lung lesions. The identification of prognostic factors can help to improve the risk stratification of patients by promptly defining for each the most effective therapy to resolve the disease. The etiological agent causing COVID-19 is a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that enters cells via the ACE2 receptor. SARS-CoV-2 infection causes a reduction in ACE2 levels, leading to an imbalance in the renin-angiotensin system (RAS), and consequently, in blood pressure and systemic vascular resistance. ERAP1 and ERAP2 are two RAS regulators and key components of MHC class I antigen processing. Their polymorphisms have been associated with autoimmune and inflammatory conditions, hypertension, and cancer. Based on their involvement in the RAS, we believe that the dysfunctional status of ERAP1 and ERAP2 enzymes may exacerbate the effect of SARS-CoV-2 infection, aggravating the symptomatology and clinical outcome of the disease. In this review, we discuss this hypothesis.


Subject(s)
Aminopeptidases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Hypertension/enzymology , Minor Histocompatibility Antigens/metabolism , Renin-Angiotensin System , SARS-CoV-2/metabolism , Age Factors , Aminopeptidases/genetics , Antigen Presentation/genetics , COVID-19/virology , Female , Humans , Hypertension/genetics , Male , Minor Histocompatibility Antigens/genetics , Polymorphism, Single Nucleotide , Sex Factors , Virus Internalization
9.
Epidemiol Prev ; 44(5-6 Suppl 2): 169-182, 2020.
Article in English | MEDLINE | ID: covidwho-1068137

ABSTRACT

As the Coronavirus situation (COVID-19) continues to evolve, many questions concerning the factors relating to the diffusion and severity of the disease remain unanswered.Whilst opinions regarding the weight of evidence for these risk factors, and the studies published so far are often inconclusive or offer contrasting results, the role of comorbidities in the risk of serious adverse outcomes in patients affected with COVID-19 appears to be evident since the outset. Hypertension, diabetes, and obesity are under discussion as important factors affecting the severity of disease. Air pollution has been considered to play a role in the diffusion of the virus, in the propagation of the contagion, in the severity of symptoms, and in the poor prognosis. Accumulating evidence supports the hypothesis that environmental particulate matter (PM) can trigger inflammatory responses at molecular, cellular, and organ levels, sustaining respiratory, cardiovascular, and dysmetabolic diseases.To better understand the intricate relationships among pre-existing conditions, PM, and viral infection, we examined the response at the molecular level of T47D human breast adenocarcinoma cells exposed to different fractions of PM. T47D cells express several receptors, including the aryl hydrocarbon receptor (AhR), and ACE2, the main - but not the only - receptor for SARS-CoV-2 entry.PM samples were collected in an urban background site located in the Northern area of the City of Bologna (Emilia-Romagna Region, Northern Italy) during winter 2013. T47D cells were exposed to organic or aqueous (inorganic) extracts at the final concentration of 8 m3 for a 4-hour duration. Both the concentration and the exposure time were chosen to resemble an average outdoor exposure. RNA was extracted from cells, purified and hybridised on 66k microarray slides from Agilent.The lists of differentially expressed genes in PM organic extracts were evaluated by using Metacore, and an enrichment analysis was performed to identify pathways maps, process networks, and disease by biomarkers altered after T47D treatment.The analysis of the modulated genes gave evidence for the involvement of PM in dysmetabolic diseases, including diabetes and obesity, and hypertension through the activation of the aryl hydrocarbon receptor (AhR) canonical pathway.On the basis of current knowledge, existing data, and exploratory experimental evidence, we tease out the likely molecular interplay that can ultimately tip the disease outcome into severity. Looking beyond ACE2, several additional key markers are identified. Disruption of these targets worsens pre-existing conditions and/or exacerbates the adverse effects induced by SARS-CoV-2 infection. Whilst appropriately designed, epidemiological studies are very much needed to investigate these associations based on our hypothesis of investigation, by reviewing recent experimental and epidemiological evidence, here we speculate and provide new insights on the possible role of environmental pollution in the exacerbation of effects by SARS-CoV-2 and other respiratory viruses. This work is intended to assist in the development of appropriate investigative approaches to protect public health.


Subject(s)
Air Pollution/adverse effects , COVID-19/epidemiology , Particulate Matter/adverse effects , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/physiology , COVID-19/etiology , Cell Line, Tumor , Comorbidity , Coronaviridae/physiology , Cytochrome P-450 CYP1A1/physiology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Susceptibility , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Hypertension/epidemiology , Hypertension/genetics , Hypertension/metabolism , Inflammation/epidemiology , Inflammation/genetics , Inflammation/metabolism , Italy , Obesity/epidemiology , Obesity/genetics , Obesity/metabolism , Particulate Matter/pharmacology , Receptors, Aryl Hydrocarbon/physiology , Receptors, Virus/physiology , Risk , SARS-CoV-2/ultrastructure , Signal Transduction
10.
Eur Heart J ; 41(48): 4580-4588, 2020 12 21.
Article in English | MEDLINE | ID: covidwho-1066303

ABSTRACT

AIMS: Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported. METHODS AND RESULTS: We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis. CONCLUSION: Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antihypertensive Agents/pharmacology , Hypertension , Kidney Tubules/metabolism , Lung/metabolism , Renin-Angiotensin System/drug effects , Adrenergic beta-Antagonists/pharmacology , Adult , Age Factors , Aged , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , COVID-19/complications , Diuretics/pharmacology , Female , Gene Expression Profiling , Glomerular Filtration Rate , Humans , Hypertension/drug therapy , Hypertension/genetics , Kidney Tubules/physiopathology , Male , Middle Aged , Rats , Rats, Inbred SHR , SARS-CoV-2 , Sequence Analysis, RNA , Sex Factors , Transcriptome/drug effects
11.
Am J Hypertens ; 34(4): 367-376, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1003506

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been identified as the entry receptor for coronaviruses into human cells, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Since hypertension (HT) is a leading comorbidity in non-survivors of COVID-19, we tested for association between ACE2 gene and HT in interaction with specific pre-existing conditions known to be associated with COVID-19 severity. METHODS: Genetic analysis of ACE2 gene was conducted in French-Canadian (FC) and British populations. RESULTS: In FC individuals, the T allele of the single nucleotide polymorphism rs2074192 of ACE2 gene was a risk factor for HT in adult obese males [odds ratio (OR) = 1.39, 95% confidence interval (CI) 1.06-1.83)] and even more so in obese males who smoked (OR = 1.67, CI: 1.24-2.55), but not in lean males, non-smoker males or females. The T allele was significantly associated with severity of HT and with earlier penetrance of HT in obese smoking males. Significant interaction between the T allele and obesity was present in both sexes. The association of ACE2 (rs233575) genotype with blood pressure was also seen in adolescents but the interaction with obesity was present only in females. Several variants in ACE2 gene were found to be associated with HT in obese, smoking males in British individuals of the UK Biobank. In addition, we observed more severe outcomes to COVID-19 in association with ACE2 risk alleles in obese, smoking males. CONCLUSIONS: This is the first report that ACE2 variants are associated with earlier penetrance and more severe HT and with more severe outcomes of COVID-19 in obese smoking males.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19 , Hypertension , Obesity , Adolescent , Blood Pressure/physiology , COVID-19/epidemiology , COVID-19/therapy , Canada/epidemiology , Comorbidity , Female , Genetic Predisposition to Disease , Humans , Hypertension/diagnosis , Hypertension/epidemiology , Hypertension/genetics , Male , Middle Aged , Obesity/diagnosis , Obesity/epidemiology , Obesity/etiology , Polymorphism, Single Nucleotide , SARS-CoV-2/physiology , Severity of Illness Index , Sex Factors , Smoking/epidemiology
12.
Nat Biotechnol ; 39(6): 705-716, 2021 06.
Article in English | MEDLINE | ID: covidwho-997913

ABSTRACT

In coronavirus disease 2019 (COVID-19), hypertension and cardiovascular diseases are major risk factors for critical disease progression. However, the underlying causes and the effects of the main anti-hypertensive therapies-angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)-remain unclear. Combining clinical data (n = 144) and single-cell sequencing data of airway samples (n = 48) with in vitro experiments, we observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses, whereas ARB treatment related to enhanced epithelial-immune cell interactions. Macrophages and neutrophils of patients with hypertension, in particular under ARB treatment, exhibited higher expression of the pro-inflammatory cytokines CCL3 and CCL4 and the chemokine receptor CCR1. Although the limited size of our cohort does not allow us to establish clinical efficacy, our data suggest that the clinical benefits of ACEI treatment in patients with COVID-19 who have hypertension warrant further investigation.


Subject(s)
COVID-19/drug therapy , Chemokine CCL3/genetics , Chemokine CCL4/genetics , Hypertension/drug therapy , Receptors, CCR1/genetics , Adult , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/adverse effects , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Disease Progression , Female , Gene Expression Regulation/drug effects , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/pathology , Inflammation/complications , Inflammation/drug therapy , Inflammation/genetics , Inflammation/virology , Male , Middle Aged , RNA-Seq , Respiratory System/drug effects , Respiratory System/pathology , Respiratory System/virology , Risk Factors , SARS-CoV-2/pathogenicity , Single-Cell Analysis
13.
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
14.
Med Hypotheses ; 146: 110448, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-969015

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is able to produce an excessive host immune reaction and may leads to severe disease- a life-threatening condition occurring more often in patients suffering from comorbidities such as hypertension, diabetes and obesity. Infection by human corona viruses highly depends on host microRNA (miR) involved in regulation of host innate immune response and inflammation-modulatory miR-146a is among the first miRs induced by immune reaction to a virus. Moreover, recent analysis showed that miR-146 is predicted to target at the SARS-CoV-2 genome. As the dominant regulator of Toll-like receptors (TLRs) downstream signaling, miR-146a may limit excessive inflammatory response to virus. Downregulation of circulating miR-146a was found in diabetes, obesity and hypertension and it is reflected by enhanced inflammation and fibrosis, systemic effects accompanying severe COVID-19. Thus it could be hypothesized that miR-146a deficiency may contribute to severe COVID-19 state observed in diabetes, obesity and hypertension but further investigations are needed.


Subject(s)
COVID-19/complications , Diabetes Mellitus/genetics , Hypertension/complications , MicroRNAs/genetics , Obesity/complications , Pandemics , SARS-CoV-2 , COVID-19/genetics , COVID-19/immunology , Diabetes Complications/genetics , Diabetes Complications/immunology , Diabetes Mellitus/immunology , Down-Regulation , Humans , Hypertension/genetics , Hypertension/immunology , Immunity, Innate/genetics , Inflammation/complications , Inflammation/genetics , Inflammation/immunology , MicroRNAs/metabolism , Models, Biological , Obesity/genetics , Obesity/immunology , Risk Factors , Severity of Illness Index
15.
Stem Cell Rev Rep ; 17(1): 94-112, 2021 02.
Article in English | MEDLINE | ID: covidwho-841111

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by novel coronavirus Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first time reported in December 2019 in Wuhan, China and thereafter quickly spread across the globe. Till September 19, 2020, COVID-19 has spread to 216 countries and territories. Severe infection of SARS-CoV-2 cause extreme increase in inflammatory chemokines and cytokines that may lead to multi-organ damage and respiratory failure. Currently, no specific treatment and authorized vaccines are available for its treatment. Renin angiotensin system holds a promising role in human physiological system specifically in regulation of blood pressure and electrolyte and fluid balance. SARS-CoV-2 interacts with Renin angiotensin system by utilizing angiotensin-converting enzyme 2 (ACE2) as a receptor for its cellular entry. This interaction hampers the protective action of ACE2 in the cells and causes injuries to organs due to persistent angiotensin II (Ang-II) level. Patients with certain comorbidities like hypertension, diabetes, and cardiovascular disease are under the high risk of COVID-19 infection and mortality. Moreover, evidence obtained from several reports also suggests higher susceptibility of male patients for COVID-19 mortality and other acute viral infections compared to females. Analysis of severe acute respiratory syndrome coronavirus (SARS) and Middle East respiratory syndrome coronavirus (MERS) epidemiological data also indicate a gender-based preference in disease consequences. The current review addresses the possible mechanisms responsible for higher COVID-19 mortality among male patients. The major underlying aspects that was looked into includes smoking, genetic factors, and the impact of reproductive hormones on immune systems and inflammatory responses. Detailed investigations of this gender disparity could provide insight into the development of patient tailored therapeutic approach which would be helpful in improving the poor outcomes of COVID-19. Graphical abstract.


Subject(s)
COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Hypertension/epidemiology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Cardiovascular Diseases/complications , Cardiovascular Diseases/genetics , Cardiovascular Diseases/virology , Diabetes Mellitus/epidemiology , Diabetes Mellitus/genetics , Diabetes Mellitus/virology , Female , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/virology , Male , Renin-Angiotensin System/genetics , Sex Characteristics
16.
Molecules ; 25(6)2020 Mar 12.
Article in English | MEDLINE | ID: covidwho-832671

ABSTRACT

The inhibition of human angiotensin I converting enzyme (ACE) has been regarded as a promising approach for the treatment of hypertension. Despite research attempts over many years, our understanding the mechanisms of activation and inhibition of ACE is still far from complete. Here, we present results of all atom molecular dynamics simulations of ACE with and without ligands. Two types of inhibitors, competitive and mixed non-competitive, were used to model the ligand bound forms. In the absence of a ligand the simulation showed spontaneous large hinge-bending motions of multiple conversions between the closed and open states of ACE, while the ligand bound forms were stable in the closed state. Our simulation results imply that the equilibrium between pre-existing backbone conformations shifts in the presence of a ligand. The hinge-bending motion of ACE is considered as an essential to the enzyme function. A mechanistic model of activation and the inhibition may provide valuable information for novel inhibitors of ACE.


Subject(s)
Hypertension/drug therapy , Peptidyl-Dipeptidase A/chemistry , Protein Binding/drug effects , Protein Conformation , Binding Sites/drug effects , Humans , Hypertension/genetics , Ligands , Molecular Dynamics Simulation , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/ultrastructure , Thermodynamics
17.
Br J Clin Pharmacol ; 87(4): 1839-1846, 2021 04.
Article in English | MEDLINE | ID: covidwho-835295

ABSTRACT

AIM: Angiotensin-converting enzyme 2 (ACE 2) is the binding domain for severe acute respiratory syndrome coronavirus (SARS-CoV) and SARSCoV-2. Some antihypertensive drugs affect ACE2 expression or activity (ACE inhibitors and angiotensin II receptor blockers [ARBs]), suggesting use of other hypertensives might be preferable, such as calcium channel blockers (CCBs). Given the limited evidence, the International Society of Hypertension does not support such a policy. METHODS: We used a Mendelian randomization study to obtain unconfounded associations of antihypertensives, instrumented by published genetic variants in genes regulating target proteins of these drugs, with immune (lymphocyte and neutrophil percentage) and inflammatory (tumour necrosis factor alpha [TNF-α]) markers in the largest available genome-wide association studies. RESULTS: Genetically predicted effects of ACE inhibitors increased lymphocyte percentage (0.78, 95% confidence interval [CI] 0.35, 1.22), decreased neutrophil percentage (-0.64, 95% CI -1.09, -0.20) and possibly lowered TNF-α (-4.92, 95% CI -8.50, -1.33). CCBs showed a similar pattern for immune function (lymphocyte percentage 0.21, 95% CI 0.05 to 0.36; neutrophil percentage -0.23, 95% CI -0.39 to -0.08) but had no effect on TNF-α, as did potassium-sparing diuretics and aldosterone antagonists, and vasodilator antihypertensives. ARBs and other classes of hypertensives had no effect on immune function or TNF-α. CONCLUSION: Varying effects of different classes of antihypertensives on immune and inflammatory markers do not suggest antihypertensive use based on their role in ACE2 expression, but instead suggest investigation of the role of antihypertensives in immune function and inflammation might reveal important information that could optimize their use in SARSCoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Immunity/drug effects , Inflammation/drug therapy , Polymorphism, Single Nucleotide , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antihypertensive Agents/adverse effects , Genome-Wide Association Study , Humans , Hypertension/enzymology , Hypertension/genetics , Immunity/genetics , Inflammation/enzymology , Inflammation/immunology , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/metabolism , Mendelian Randomization Analysis , Neutrophils/drug effects , Neutrophils/immunology , Neutrophils/metabolism , Tumor Necrosis Factor-alpha/metabolism
18.
Stem Cell Rev Rep ; 17(1): 132-143, 2021 02.
Article in English | MEDLINE | ID: covidwho-692570

ABSTRACT

Severe acute respiratory syndrome corona virus - 2 (SARS-CoV-2) is a single stranded RNA virus and responsible for infecting human being. In many cases the individual may remain asymptomatic. Some recently reported studies revealed that individuals of elderly age group and with pre-existing medical conditions such as hypertension, diabetes mellitus had severe consequences, even may lead to death. However, it is not clearly delineated whether hypertension itself or associated comorbidities or antihypertensive therapy contributes to the grave prognosis of COVID-19 infections. This review is aimed to decipher the exact mechanisms involved at molecular level from existing evidence and as reported. It has been reported that SARS-CoV-2 enters into the host cell through interaction between conserved residues of viral spike protein and angiotensin converting enzyme 2 (ACE2) receptor which is highly expressed in host's cardiac and pulmonary cells and finally transmembrane protease, serine-2 (TMPRSS2), helps in priming of the surface protein. Subsequently, symptom related to multi organ involvement is primarily contributed by cytokine storm. Although various clinical trials are being conducted on renin- angiotensin- system inhibitor, till to date there is no standard treatment protocol approved for critically ill COVID-19 positive cases with pre-existing hypertension. Recently, several studies are carried out to document the safety and efficacy outcome of mesenchymal stem cell transplantation based on its immunomodulatory and regenerative properties. Therefore, identification of future novel therapeutics in the form of mesenchymal stem cell either alone or in combination with pharmacological approach could be recommended for combating SARS-CoV-2 which might be dreadful to debilitating elderly people. Graphical Abstract.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/therapy , Hypertension/therapy , SARS-CoV-2/genetics , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Humans , Hypertension/genetics , Hypertension/pathology , Hypertension/virology , Mesenchymal Stem Cells/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics
19.
J Cell Mol Med ; 24(16): 9478-9482, 2020 08.
Article in English | MEDLINE | ID: covidwho-635772

ABSTRACT

Recent retrospective studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) revealed that the patients with common comorbidities of cancers and chronic diseases face significantly poorer clinical outcomes than those without. Since the expression profile of ACE2, a crucial cell entry receptor for SARS-CoV-2, could indicate the susceptibility to SARS-CoV-2 infection, here we systematically dissected ACE2 expression using large-scale multi-omics data from 30 organs/tissues, 33 cancer types and some common chronic diseases involving >28 000 samples. It was found that sex and age could be correlated with the susceptibility of SARS-CoV-2 infection for certain tissues. Strikingly, ACE2 was up-regulated in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, oesophageal carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma and uterine corpus endometrial carcinoma compared to controls. Furthermore, the patients with common chronic diseases regarding angiocardiopathy, type 2 diabetes, liver, pneumonia and hypertension were also with higher ACE2 expression compared to related controls, which were validated using independent data sets. Collectively, our study may reveal a novel important mechanism that the patients with certain cancers and chronic diseases may express higher ACE2 expression compared to the individuals without diseases, which could lead to their higher susceptibility to multi-organ injury of SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Neoplasms/metabolism , Receptors, Virus/metabolism , Adult , Age Factors , Aged , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , COVID-19/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Female , Gene Expression Regulation/genetics , Gene Expression Regulation, Neoplastic/genetics , Gene Regulatory Networks , Humans , Hypertension/genetics , Hypertension/metabolism , Male , Middle Aged , Neoplasms/genetics , Pneumonia/genetics , Pneumonia/metabolism , Retrospective Studies , Risk Factors , Sex Factors , Up-Regulation
20.
J Infect Dis ; 222(4): 556-563, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-593365

ABSTRACT

Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.


Subject(s)
Coronavirus Infections/epidemiology , Lung/enzymology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Angiotensin-Converting Enzyme 2 , COVID-19 , Case-Control Studies , Cerebrovascular Disorders/epidemiology , Cerebrovascular Disorders/genetics , Comorbidity , Coronary Disease/epidemiology , Coronary Disease/genetics , Coronavirus Infections/enzymology , Coronavirus Infections/genetics , Diabetes Complications/epidemiology , Diabetes Complications/genetics , Epigenomics , Female , Humans , Hypertension/epidemiology , Hypertension/genetics , Male , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/enzymology , Pneumonia, Viral/genetics , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/genetics , Severity of Illness Index , Systems Biology , Transcriptome
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