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2.
In Vivo ; 36(1): 13-29, 2022.
Article in English | MEDLINE | ID: covidwho-1593602

ABSTRACT

Chronic and acute respiratory diseases pose a major problem for public health worldwide due to the high morbidity and mortality rates, while treatment options remain mostly symptomatic. The renin-angiotensin system (RAS) plays an important role in lung tissue, regulating pulmonary circulation and blood pressure, but also contributing to normal pulmonary function and development. Angiotensin-converting enzyme (ACE) and its homologous angiotensin-converting enzyme 2 (ACE2) are considered to be amongst the main RAS regulators and are highly expressed in the pulmonary vascular endothelium. This review discusses the impact of ACE and ACE2 functional gene polymorphisms on seven major pulmonary diseases, in terms of predisposition, course, and outcome, revealing their potential utility as both genetic markers and biomarkers. The discussed conditions include chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), lung cancer and pulmonary sarcoidosis (PS), as well as SARS-CoV-2 viral infection and COVID-19 disease.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Peptidyl-Dipeptidase A , Humans , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , Renin-Angiotensin System/genetics , SARS-CoV-2
3.
Molecules ; 26(22)2021 Nov 17.
Article in English | MEDLINE | ID: covidwho-1524085

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.


Subject(s)
COVID-19/virology , Renin-Angiotensin System/genetics , SARS-CoV-2/physiology , COVID-19/genetics , Habits , Humans , Life Style , Polymorphism, Genetic , Sex Factors
4.
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
5.
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
6.
OMICS ; 25(7): 408-416, 2021 07.
Article in English | MEDLINE | ID: covidwho-1287972

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is anticipated to transition to an endemic state as vaccines are providing relief in some, but not all, countries. Drug discovery for COVID-19 can offer another tool in the fight against the pandemic. Additionally, COVID-19 impacts multiple organs that call for a systems medicine approach to planetary health and therapeutics innovation. In this context, innovation for drugs that prevent and treat COVID-19 is timely and much needed. As the virus variants emerge under different ecological conditions and contexts in the long haul, a broad array of vaccine and drug options will be necessary. This expert review article argues for a need to expand the COVID-19 interventions, including and beyond vaccines, to stimulate discovery and development of novel medicines against SARS-CoV-2 infection. The Renin-Angiotensin-Aldosterone System (RAAS) is known to play a major role in SARS-CoV-2 infection. Neprilysin (NEP) and angiotensin-converting enzyme (ACE) have emerged as the pharmaceutical targets of interest in the search for therapeutic interventions against COVID-19. While the NEP/ACE inhibitors offer promise for repurposing against COVID-19, they may display a multitude of effects in different organ systems, some beneficial, and others adverse, in modulating the inflammation responses in the course of COVID-19. This expert review offers an analysis and discussion to deepen our present understanding of the pathophysiological function of neprilysin in multiple organs, and the possible effects of NEP inhibitor-induced inflammatory responses in COVID-19-infected patients.


Subject(s)
Neprilysin/chemistry , Bradykinin/genetics , Bradykinin/metabolism , Renin-Angiotensin System/genetics , Renin-Angiotensin System/physiology , SARS-CoV-2
7.
J Mol Med (Berl) ; 99(7): 899-915, 2021 07.
Article in English | MEDLINE | ID: covidwho-1171990

ABSTRACT

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has proven a challenge to healthcare systems since its first appearance in late 2019. The global spread and devastating effects of coronavirus disease 2019 (COVID-19) on patients have resulted in countless studies on risk factors and disease progression. Overweight and obesity emerged as one of the major risk factors for developing severe COVID-19. Here we review the biology of coronavirus infections in relation to obesity. In particular, we review literature about the impact of adiposity-related systemic inflammation on the COVID-19 disease severity, involving cytokine, chemokine, leptin, and growth hormone signaling, and we discuss the involvement of hyperactivation of the renin-angiotensin-aldosterone system (RAAS). Due to the sheer number of publications on COVID-19, we cannot be completed, and therefore, we apologize for all the publications that we do not cite.


Subject(s)
COVID-19/genetics , Inflammation/genetics , Obesity/genetics , SARS-CoV-2/genetics , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Disease Progression , Humans , Inflammation/complications , Inflammation/pathology , Inflammation/virology , Obesity/complications , Obesity/pathology , Obesity/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Renin-Angiotensin System/genetics , Risk Factors , SARS-CoV-2/pathogenicity
8.
Biol Open ; 10(3)2021 03 23.
Article in English | MEDLINE | ID: covidwho-1148236

ABSTRACT

People with underlying conditions, including hypertension, obesity, and diabetes, are especially susceptible to negative outcomes after infection with coronavirus SARS-CoV-2, which causes COVID-19. Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from rapidly dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II, counteracting its chronic effects, and serves as the SARS-CoV-2 receptor. Ace, the coronavirus, and COVID-19 comorbidities all regulate Ace2, but we do not yet understand how. To exploit zebrafish (Danio rerio) to help understand the relationship of the RAAS to COVID-19, we must identify zebrafish orthologs and co-orthologs of human RAAS genes and understand their expression patterns. To achieve these goals, we conducted genomic and phylogenetic analyses and investigated single cell transcriptomes. Results showed that most human RAAS genes have one or more zebrafish orthologs or co-orthologs. Results identified a specific type of enterocyte as the specific site of expression of zebrafish orthologs of key RAAS components, including Ace, Ace2, Slc6a19 (SARS-CoV-2 co-receptor), and the Angiotensin-related peptide cleaving enzymes Anpep (receptor for the common cold coronavirus HCoV-229E), and Dpp4 (receptor for the Middle East Respiratory Syndrome virus, MERS-CoV). Results identified specific vascular cell subtypes expressing Ang II receptors, apelin, and apelin receptor genes. These results identify genes and cell types to exploit zebrafish as a disease model for understanding mechanisms of COVID-19.


Subject(s)
Enterocytes , Gene Expression Regulation , Renin-Angiotensin System/genetics , SARS-CoV-2 , Zebrafish Proteins , Zebrafish , Animals , COVID-19/genetics , COVID-19/metabolism , Disease Models, Animal , Enterocytes/metabolism , Enterocytes/virology , Humans , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish/virology , Zebrafish Proteins/biosynthesis , Zebrafish Proteins/genetics
9.
Cells ; 10(3)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1136461

ABSTRACT

Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1-7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Receptors, Angiotensin/metabolism , Renin-Angiotensin System/drug effects , Aging/metabolism , Aging/pathology , Animals , Autoimmunity/drug effects , Autoimmunity/genetics , COVID-19/drug therapy , COVID-19/genetics , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Humans , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Receptors, Angiotensin/genetics , Regeneration/drug effects , Regeneration/genetics , Regeneration/physiology , Renin-Angiotensin System/genetics , Renin-Angiotensin System/physiology , Vulvodynia/immunology , Vulvodynia/physiopathology
10.
Iran J Allergy Asthma Immunol ; 19(5): 456-470, 2020 Oct 18.
Article in English | MEDLINE | ID: covidwho-1068112

ABSTRACT

The new coronavirus, known as "SARS-CoV-2"; is the cause of one of the most prevalent infectious viral diseases that was recently announced pandemic by the world health organization. Ongoing research in the fields of prevention, management, and therapy establishes a functional scaffold for clinics during the time of crisis. To obtain this goal, it is necessary that all pathophysiologic aspects of COVID-19 from infection to predisposing backgrounds of infection be identified, so that all the ambiguities of researchers regarding transmission mechanisms, variable clinical manifestation, and therapeutic response can be solved. Here, we firstly discuss about the homology screening between nCoV-2019 and beta-coronavirus family using phylogenetic analyses. Secondly, we analyzed the viral motifs to show that viral entry into the host cells requires a primary activation step performed by FURIN and FURIN-like-mediated enzymatic cleavage on the structural glycoprotein. The cleavage increases viral performance by 1000 folds. We then present a comprehensive view on host cells and the significance of gene variants affecting activation enzymes, supportive entry, and spread mechanisms in humans including renin-angiotensin-aldosterone system (RAAS) a pathway results in certain phenotypes or exacerbate infection-related phenotypes in different organs, hence causes variable clinical manifestations. This is followed by discussing about the importance of personalized medicine in nCoV-2019 exposure. Moreover, chemical drugs prescribed for individuals affected with COVID-19, as well as genes involved in drug transport and metabolisms are reviewed as a prelude to drug response. Finally, we suggest some therapeutic approaches developed based on new methods and technology such as anti-sense therapy and antibodies.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Furin/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , ADAM17 Protein/genetics , ADAM17 Protein/metabolism , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Betacoronavirus/genetics , COVID-19/drug therapy , COVID-19/physiopathology , COVID-19/transmission , Enzyme Inhibitors/therapeutic use , Furin/metabolism , Genetic Predisposition to Disease , Genome, Human , Genome, Viral , Humans , Hydroxychloroquine/therapeutic use , Phylogeny , Precision Medicine , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , Renin-Angiotensin System/genetics , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
11.
Peptides ; 137: 170477, 2021 03.
Article in English | MEDLINE | ID: covidwho-1001641

ABSTRACT

After decades of notoriety for its adverse cardiovascular, proinflammatory and profibrotic actions, the renin-angiotensin system (RAS) began to be cast in a more favorable light with the discovery of angiotensin-converting enzyme-2 (ACE2) in 2000. This monocarboxypeptidase, best known for its ability to metabolize angiotensin (Ang) II to Ang 1-7, counteracts the adverse effects of Ang II mediated by the AT1 Ang II receptor. Ang peptides are classically considered to be metabolized by aminopeptidases, by which the nomenclature Ang III (des-Asp1Ang II, 2-8 heptapeptide) and Ang IV (des-Asp1des-Arg2Ang II, 3-8 hexapeptide) are derived. This report compares the ability of recombinant human ACE2 (rhACE2) to metabolize Ang III, Ang IV and Ang V, (4-8 pentapeptide) relative to Ang II to form corresponding des-omega-Phe metabolites. rhACE2 has highest affinity (lowest Km) for Ang III, followed by Ang II ∼ Ang V, followed by Ang IV. However, rhACE2 has the highest Kcat for metabolising Ang IV followed by Ang V, Ang III and Ang II. The enzymatic efficiency (Kcat/Km) is highest for Ang V and Ang III followed by Ang IV and is lowest for Ang II. As a gluzincin metallopeptidase, ACE2 requires a zinc molecule at its active site for catalysis. This report also documents inhibition of ACE2 activity by concentrations of zinc exceeding 10 µM. These observations extend the functional significance of ACE2 to include the metabolic inactivation of Ang III, Ang IV and Ang V, reemphasizing the importance of monitoring zinc intake to maintain metabolic homeostasis.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Angiotensins/metabolism , Peptides/metabolism , Recombinant Proteins/metabolism , Aminopeptidases/genetics , Aminopeptidases/metabolism , Angiotensin I/genetics , Angiotensin I/metabolism , Angiotensin II/analogs & derivatives , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensins/genetics , Humans , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptides/genetics , Peptidyl-Dipeptidase A/genetics , Recombinant Proteins/genetics , Renin-Angiotensin System/genetics , Zinc/pharmacology
12.
Signal Transduct Target Ther ; 5(1): 293, 2020 12 24.
Article in English | MEDLINE | ID: covidwho-997815

ABSTRACT

On 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.


Subject(s)
COVID-19/epidemiology , Endothelial Cells/virology , Inflammation/epidemiology , Pandemics , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Endothelial Cells/pathology , Humans , Inflammation/virology , Renin-Angiotensin System/genetics , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
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
15.
Ther Adv Cardiovasc Dis ; 14: 1753944720977715, 2020.
Article in English | MEDLINE | ID: covidwho-962356

ABSTRACT

COVID-19 is said to be a pandemic that does not distinguish between skin color or ethnic origin. However, data in many parts of the world, especially in the United States, begin to show that there is a sector of society suffering a more significant impact from this pandemic. The Black population is more vulnerable than the White population to infection and death by COVID-19, with hypertension and diabetes mellitus as probable predisposing factors. Over time, multiple disparities have been observed between the health of Black and White populations, associated mainly with socioeconomic inequalities. However, some mechanisms and pathophysiological susceptibilities begin to be elucidated that are related directly to the higher prevalence of multiple diseases in the Black population, including infection and death by COVID-19. Plasma vitamin D levels and evolutionary adaptations of the renin-angiotensin-aldosterone system (RAAS) in Black people differ considerably from those of other races. The role of these factors in the development and progression of hypertension and multiple lung diseases, among them SARS-CoV-2 infection, is well established. In this sense, the present review attempts to elucidate the link between vitamin D and RAAS ethnic disparities and susceptibility to infection and death by COVID-19 in Black people, and suggests possible mechanisms for this susceptibility.


Subject(s)
African Americans/genetics , COVID-19/mortality , Health Status Disparities , Renin-Angiotensin System/genetics , Social Determinants of Health/ethnology , Socioeconomic Factors , Vitamin D Deficiency/mortality , Vitamin D/analogs & derivatives , Biomarkers/blood , COVID-19/ethnology , COVID-19/genetics , Genetic Predisposition to Disease , Humans , Race Factors , Risk Assessment , Risk Factors , United States/epidemiology , Vitamin D/blood , Vitamin D Deficiency/blood , Vitamin D Deficiency/ethnology
16.
Am J Physiol Heart Circ Physiol ; 320(1): H296-H304, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-961166

ABSTRACT

Biological sex is increasingly recognized as a critical determinant of health and disease, particularly relevant to the topical COVID-19 pandemic caused by the SARS-CoV-2 coronavirus. Epidemiological data and observational reports from both the original SARS epidemic and the most recent COVID-19 pandemic have a common feature: males are more likely to exhibit enhanced disease severity and mortality than females. Sex differences in cardiovascular disease and COVID-19 share mechanistic foundations, namely, the involvement of both the innate immune system and the canonical renin-angiotensin system (RAS). Immunological differences suggest that females mount a rapid and aggressive innate immune response, and the attenuated antiviral response in males may confer enhanced susceptibility to severe disease. Furthermore, the angiotensin-converting enzyme 2 (ACE2) is involved in disease pathogenesis in cardiovascular disease and COVID-19, either to serve as a protective mechanism by deactivating the RAS or as the receptor for viral entry, respectively. Loss of membrane ACE2 and a corresponding increase in plasma ACE2 are associated with worsened cardiovascular disease outcomes, a mechanism attributed to a disintegrin and metalloproteinase (ADAM17). SARS-CoV-2 infection also leads to ADAM17 activation, a positive feedback cycle that exacerbates ACE2 loss. Therefore, the relationship between cardiovascular disease and COVID-19 is critically dependent on the loss of membrane ACE2 by ADAM17-mediated proteolytic cleavage. This article explores potential mechanisms involved in COVID-19 that may contribute to sex-specific susceptibility focusing on the innate immune system and the RAS, namely, genetics and sex hormones. Finally, we highlight here the added challenges of gender in the COVID-19 pandemic.


Subject(s)
Adaptive Immunity/immunology , Androgens/immunology , Angiotensin-Converting Enzyme 2/genetics , COVID-19/immunology , Estrogens/immunology , Immunity, Innate/immunology , Receptors, Coronavirus/genetics , ADAM17 Protein/metabolism , Adaptive Immunity/genetics , Androgens/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Estrogens/metabolism , Female , Genes, X-Linked/genetics , Genes, X-Linked/immunology , Humans , Immunity, Innate/genetics , Male , Promoter Regions, Genetic , Receptors, Coronavirus/metabolism , Renin-Angiotensin System/genetics , Renin-Angiotensin System/immunology , Response Elements/genetics , SARS-CoV-2/metabolism , Severity of Illness Index , Sex Characteristics , Sex Factors , X Chromosome Inactivation
17.
Sci Rep ; 10(1): 19522, 2020 11 11.
Article in English | MEDLINE | ID: covidwho-920619

ABSTRACT

SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin-kallikrein system, resulting in acute lung inflammatory edema; the renin-angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.


Subject(s)
Betacoronavirus/genetics , Blood Coagulation , Gene Expression Profiling , Kallikrein-Kinin System/genetics , Peptidyl-Dipeptidase A/genetics , Pulmonary Alveoli/cytology , Renin-Angiotensin System/genetics , Angiotensin-Converting Enzyme 2 , Betacoronavirus/enzymology , Betacoronavirus/physiology , Humans , Pulmonary Alveoli/metabolism , SARS-CoV-2 , Serine Endopeptidases/genetics
18.
Braz. arch. biol. technol ; 63: e20200304, 2020. tab, graf
Article in English | WHO COVID, LILACS (Americas) | ID: covidwho-914314

ABSTRACT

Abstract We aimed to analyze the expression profile of ACE2 and similar genes with ACE2, predict the number of variations in ACE2, detect the suspected SNPs on ACE2 gene, and perform the pathway analysis of renin-angiotensin system (RAS) and protein absorption-digestion. Moreover, we have predicted the gene-related diseases with ACE2. STRING was used to analyze functionally similar genes with ACE2. Exome Variant Server, SIFT, Polyphen2 were used to predict the number of variations in ACE2 and detect the suspected SNPs on ACE2. KEGG database and STRING were used to draw pathway of ACE2. Then, DISEASES resource, FitSNPs, UniProt, BioXpress, IGV Browser, Ensembl Genome Browser, and UCSC Genome Browser were used to predict the ACE2 gene-related diseases and expression profile in human normal and cancer tissues. We have shown that expression of ACE2 was correlated with AGT, REN, AGTR1, AGRT2, MME2, DPP4, PRCP, MEP1A, XPNPEP2, MEP1BandACE2 is expressed in testis, kidney, heart, thyroid, colon, esophagus, breast, minor salivary gland, pancreas, lung, liver, bladder, cervix, and muscle tissues. We found 99 variations in ACE2 gene, in which no previous study has been performed. In the future, this in silico analysis should be combined with other pieces of evidence including experimental data to assign function.


Subject(s)
Humans , Pneumonia, Viral/enzymology , Coronavirus Infections/enzymology , Peptidyl-Dipeptidase A/genetics , Pandemics , Renin-Angiotensin System/genetics , Gene Expression , Genotype
19.
Life Sci ; 264: 118676, 2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-899288

ABSTRACT

Angiotensin-converting enzyme 2 (ACE 2) is a membrane-bound enzyme that cleaves angiotensin II (Ang II) into angiotensin (1-7). It also serves as an important binding site for SARS-CoV-2, thereby, facilitating viral entry into target host cells. ACE 2 is abundantly present in the intestine, kidney, heart, lungs, and fetal tissues. Fetal ACE 2 is involved in myocardium growth, lungs and brain development. ACE 2 is highly expressed in pregnant women to compensate preeclampsia by modulating angiotensin (1-7) which binds to the Mas receptor, having vasodilator action and maintain fluid homeostasis. There are reports available on Zika, H1N1 and SARS-CoV where these viruses have shown to produce fetal defects but very little is known about SARS-CoV-2 involvement in pregnancy, but it might have the potential to interact with fetal ACE 2 and enhance COVID-19 transmission to the fetus, leading to fetal morbidity and mortality. This review sheds light on a path of SARS-CoV-2 transmission risk in pregnancy and its possible link with fetal ACE 2.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , Pandemics , Placenta/virology , Receptors, Virus/genetics , Spike Glycoprotein, Coronavirus/genetics , Adult , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/mortality , COVID-19/virology , Female , Fetal Mortality/trends , Fetus , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Kidney/virology , Models, Molecular , Pregnancy , Protein Structure, Secondary , Receptors, Virus/chemistry , Receptors, Virus/metabolism , Renin-Angiotensin System/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Uterus/virology
20.
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
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