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1.
J Am Heart Assoc ; 11(11): e025289, 2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1874925

ABSTRACT

Background Renin-angiotensin aldosterone system (RAAS) inhibitor-COVID-19 studies, observational in design, appear to use biased methods that can distort the interaction between RAAS inhibitor use and COVID-19 risk. This study assessed the extent of bias in that research and reevaluated RAAS inhibitor-COVID-19 associations in studies without critical risk of bias. Methods and Results Searches were performed in MEDLINE, EMBASE, and CINAHL databases (December 1, 2019 to October 21, 2021) identifying studies that compared the risk of infection and/or severe COVID-19 outcomes between those using or not using RAAS inhibitors (ie, angiotensin-converting enzyme inhibitors or angiotensin II type-I receptor blockers). Weighted hazard ratios (HR) and 95% CIs were extracted and pooled in fixed-effects meta-analyses, only from studies without critical risk of bias that assessed severe COVID-19 outcomes. Of 169 relevant studies, 164 had critical risks of bias and were excluded. Ultimately, only two studies presented data relevant to the meta-analysis. In 1 351 633 people with uncomplicated hypertension using a RAAS inhibitor, calcium channel blocker, or thiazide diuretic in monotherapy, the risk of hospitalization (angiotensin-converting enzyme inhibitor: HR, 0.76; 95% CI, 0.66-0.87; P<0.001; angiotensin II type-I receptor blockers: HR, 0.86; 95% CI, 0.77-0.97; P=0.015) and intubation or death (angiotensin-converting enzyme inhibitor: HR, 0.64; 95% CI, 0.48-0.85; P=0.002; angiotensin II type-I receptor blockers: HR, 0.74; 95% CI, 0.58-0.95; P=0.019) with COVID-19 was lower in those using a RAAS inhibitor. However, these protective effects are probably not clinically relevant. Conclusions This study reveals the critical risk of bias that exists across almost an entire body of COVID-19 research, raising an important question: Were research methods and/or peer-review processes temporarily weakened during the surge of COVID-19 research or is this lack of rigor a systemic problem that also exists outside pandemic-based research? Registration URL: www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021237859.


Subject(s)
COVID-19 , Hypertension , Aldosterone , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin Receptor Antagonists/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antihypertensive Agents/therapeutic use , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/epidemiology , Renin , Renin-Angiotensin System , SARS-CoV-2
2.
Life Sci ; 293: 120284, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1620913

ABSTRACT

AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the renin-angiotensin system (RAS) recently identified as the membrane receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we aim to study whether two receptors from RAS, the angiotensin receptor type 1 (AT1R) and the bradykinin 2 receptor (B2R) modulate ACE2 internalization induced by a recombinant receptor binding domain (RBD) of SARS-CoV-2 spike protein. Also, we investigated the impact of ACE2 coexpression on AT1R and B2R functionality. MATERIALS AND METHODS: To study ACE2 internalization, we assessed the distribution of green fluorescent protein (GFP) signal in HEK293T cells coexpressing GFP-tagged ACE2 and AT1R, or B2R, or AT1R plus B2R in presence of RBD alone or in combination with AT1R or B2R ligands. To estimate ACE2 internalization, we classified GFP signal distribution as plasma membrane uniform GFP (PMU-GFP), plasma membrane clustered GFP (PMC-GFP) or internalized GFP and calculated its relative frequency. Additionally, we investigated the effect of ACE2 coexpression on AT1R and B2R inhibitory action on voltage-gated calcium channels (CaV2.2) currents by patch-clamp technique. KEY FINDINGS: RBD induced ACE2-GFP internalization in a time-dependent manner. RBD-induced ACE2-GFP internalization was increased by angiotensin II and reduced by telmisartan in cells coexpressing AT1R. RBD-induced ACE2-GFP internalization was strongly inhibited by B2R co-expression. This effect was mildly modified by bradykinin and rescued by angiotensin II in presence of AT1R. ACE2 coexpression impacted on B2R- and AT1R-mediated inhibition of CaV2.2 currents. SIGNIFICANCE: Our work contributes to understand the role of RAS modulators in the susceptibility to SARS-CoV-2 infection and severity of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , Receptor, Angiotensin, Type 1/biosynthesis , Receptor, Bradykinin B2/biosynthesis , Spike Glycoprotein, Coronavirus/administration & dosage , Angiotensin II/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2/analysis , Green Fluorescent Proteins/analysis , Green Fluorescent Proteins/biosynthesis , HEK293 Cells , Humans , Receptor, Angiotensin, Type 1/analysis , Receptor, Bradykinin B2/analysis , Recombinant Proteins/administration & dosage
3.
J Pharm Pharm Sci ; 24: 390-399, 2021.
Article in English | MEDLINE | ID: covidwho-1329250

ABSTRACT

PURPOSE: SARS-CoV-2 infection is associated with substantial mortality and high morbidity. This study tested the effect of angiotensin II type I receptor blocker, losartan, on SARS-CoV-2 replication and inhibition of the papain-like protease of the virus. METHODS: The dose-dependent inhibitory effect of losartan, in concentrations from 1µM to 100µM as determined by quantitative cell analysis combining fluorescence microscopy, image processing, and cellular measurements (Cellomics analysis) on SARS-CoV-2 replication was investigated in Vero E6 cells. The impact of losartan on deubiquitination and deISGylation of SARS-CoV-2 papain-like protease (PLpro) were also evaluated.  Results: Losartan reduced PLpro cleavage of tetraUbiquitin to diUbiquitin.  It was less effective in inhibiting PLpro's cleavage of ISG15-AMC than Ubiquitin-AMC.  To determine if losartan inhibited SARS-CoV-2 replication, losartan treatment of SARS-CoV-2 infected Vero E6 was examined. Losartan treatment one hour prior to SARS-CoV-2 infection reduced levels of SARS-CoV-2 nuclear protein, an indicator of virus replication, by 80% and treatment one-hour post-infection decreased viral replication by 70%. CONCLUSION: Losartan was not an effective inhibitor of deubiquitinase or deISGylase activity of the PLpro but affected the SARS-CoV-2 replication of Vero E6 cells in vitro.  As losartan has a favorable safety profile and is currently available it has features necessary for efficacious drug repurposing and treatment of COVID-19.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Antiviral Agents/pharmacology , Losartan/pharmacology , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , Chlorocebus aethiops , Computational Biology , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/metabolism , Deubiquitinating Enzymes/antagonists & inhibitors , Deubiquitinating Enzymes/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Ubiquitin/metabolism , Vero Cells , Virus Replication/drug effects
4.
Cells ; 10(7)2021 07 11.
Article in English | MEDLINE | ID: covidwho-1308299

ABSTRACT

Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.


Subject(s)
COVID-19/metabolism , Renin-Angiotensin System , SARS-CoV-2/physiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/drug therapy , COVID-19/pathology , Drug Discovery , Humans , Molecular Targeted Therapy , Renin-Angiotensin System/drug effects , SARS-CoV-2/drug effects
5.
Obesity (Silver Spring) ; 29(9): 1423-1426, 2021 09.
Article in English | MEDLINE | ID: covidwho-1217406

ABSTRACT

OBJECTIVE: Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) uses the host's angiotensin-converting enzyme 2 (ACE2) as a cellular entry point. Therefore, modulating ACE2 might impact SARS-CoV-2 viral replication, shedding, and coronavirus disease 2019 (COVID-19) severity. Here, it was investigated whether the angiotensin II type 1 receptor blocker valsartan alters the expression of renin-angiotensin system (RAS) components, including ACE2, in human adipose tissue (AT) and skeletal muscle. METHODS: A randomized, double-blind, placebo-controlled clinical trial was performed, in which 36 participants (BMI 31.0 ± 0.8 kg/m2 ) with impaired glucose metabolism received either valsartan or placebo for 26 weeks. Before and after 26 weeks' treatment, abdominal subcutaneous AT and skeletal muscle biopsies were obtained, and gene expression of RAS components was measured by quantitative reverse transcription polymerase chain reaction. RESULTS: Valsartan treatment did not significantly impact the expression of RAS components, including ACE2, in AT and skeletal muscle. CONCLUSIONS: Given the pivotal role of ACE2 in SARS-CoV-2 spread and the clinical outcomes in COVID-19 patients, the data suggest that the putative beneficial effects of angiotensin II type 1 receptor blockers on the clinical outcomes of patients with COVID-19 may not be mediated through altered ACE2 expression in abdominal subcutaneous AT.


Subject(s)
Angiotensin II Type 1 Receptor Blockers , Angiotensin-Converting Enzyme 2/metabolism , Renin-Angiotensin System , Valsartan , Adipose Tissue/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , COVID-19 , Humans , Muscle, Skeletal/metabolism , Valsartan/pharmacology
6.
FASEB J ; 35(3): e21419, 2021 03.
Article in English | MEDLINE | ID: covidwho-1075599

ABSTRACT

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Losartan/pharmacology , SARS-CoV-2 , ADAM17 Protein/genetics , ADAM17 Protein/metabolism , Angiotensin II/administration & dosage , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin-Converting Enzyme 2/genetics , Animals , Furin/genetics , Furin/metabolism , Gene Expression Regulation, Enzymologic/drug effects , Losartan/administration & dosage , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Vasoconstrictor Agents/pharmacology
7.
Epidemiol Prev ; 44(5-6 Suppl 2): 226-234, 2020.
Article in English | MEDLINE | ID: covidwho-1068143

ABSTRACT

OBJECTIVES: to describe the clinical and demographical characteristics of COVID-19 infected people in the Friuli Venezia Giulia Region (FVG, Northern Italy). DESIGN: retrospective cohort study with an individual level record linkage procedure of different administrative databases. SETTING AND PARTICIPANTS: the cohort included 3,010 patients residing in FVG who tested positive for COVID-19 between 1 March and 15 May 2020, 2020. Regional hospital admissions and deaths without hospital admissions up to June 1st, 2020 were analysed. Determinants of the probability of a highly severe illness were investigated in terms of hospitalisations or death without hospital admission. MAIN OUTCOME MEASURES: COVID-19 patients were identified from regional epidemiological data warehouse. Demographical and clinical variables such as gender, age, patient's comorbidities, vaccinations, ARBs/sartans prescriptions, and geographical residence variables were collected by linking different databases. Descriptive analyses were performed. Logistic multivariate regressions were used to estimate the probability of hospitalisation or death, whichever came first. Model coefficients and odds ratios (OR) were reported. RESULTS: COVID-19 population in FVG had a mean age of 60 years and 59% were females. The study found that 37% had hypertension while patients with cardiologic diseases, diabetes, and cancer were around 15%; 22% of the cases were residing in retirement homes. Approximately 30% received flu or pneumococcal vaccination and a similar proportion of patients had at least one prescription of ARBs /sartans in the previous 6 months. Statistical models showed a higher probability of a worst course of disease for males, elderly, highly complicated (in terms of resource use) subjects, in the presence of cardiologic diseases, diabetes, and pneumococcal vaccination. People living in retirement homes had a lower probability of hospitalisation/death without hospital admission. The cohort was divided into two groups: COVID-19 patients infected in the territory and infected in retirement homes. Among COVID-19 patients infected in the territory, the probability of hospitalisation/death was higher for males, for older individuals, and for those with comorbidities. Diabetes resulted to be a risk factor (OR 1.79; 95%CI 1.23-2.62), as well as pneumococcal vaccination (OR 1.64; 95%CI: 1.18-2.29), which is a likely proxy of fragile patients with pulmonary disease. The flu vaccination showed a potential protective effect with a 40% lower probability of hospitalisation or death (OR 0.62; 95%CI 0.44-0.85). Among the retirement homes cohort group, a higher probability of a bad course of disease emerged for males and for more complex patients. CONCLUSIONS: the greatest risk of hospitalisation/death as a measure of more severe illness was confirmed for males, elderly, and for individuals with comorbidities. Flu vaccination seemed to have had a protective effect while pneumococcal vaccination likely identified a group of high-risk patients to be actively monitored. For patients infected in the territory, different hospitalisation strategies were implemented by the regional health districts.


Subject(s)
COVID-19/epidemiology , Pandemics , Age Distribution , Aged , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin Receptor Antagonists/pharmacology , Catchment Area, Health , Comorbidity , Databases, Factual , Female , Homes for the Aged/statistics & numerical data , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Italy/epidemiology , Male , Medical Record Linkage , Middle Aged , Multivariate Analysis , Pneumococcal Vaccines , Residence Characteristics , Retrospective Studies , Sex Distribution , Vaccination/statistics & numerical data
8.
Eur J Pharmacol ; 896: 173899, 2021 Apr 05.
Article in English | MEDLINE | ID: covidwho-1051615

ABSTRACT

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) outbreak is a major public health concern, which has accounted for >1.7 million deaths across the world. A surge in the case fatality ratio as compared with the infection ratio has been observed in most of the countries. The novel Coronavirus SARS-CoV-2 shares the most common sequence with SARS-CoV, but it has a higher rate of transmission. The SARS-CoV-2 pathogenesis is initiated by the binding of viral spike protein with the target receptor Angiotensin-Converting Enzyme 2 (ACE2) facilitating virus internalization within host cells. SARS-CoV-2 mainly causes alveolar damage ranging from mild to severe clinical respiratory manifestations. Most of the cases have revealed the association of Coronavirus disease with patients having earlier comorbidities like Hypertension, Diabetes mellitus, and Cerebrovascular diseases. Pharmacological investigation of the SARS-Cov-2 patients has revealed the frequent use of drugs belongs to Angiotensin-converting enzyme inhibitors (ACEi) and/or Angiotensin II type I receptor blockers (ARBs). Interestingly, a significant increase in ACE2 expression was noticed in patients routinely treated with the above group of drugs were also reported. To date, the association of ACEi and/or ARBs with the up-regulation of ACE2 expression has not been defined distinctively. The proposed review will focus on the pathways which are responsible for the upregulation of ACE2 and its impact on gravity of SARS-CoV-2 disease.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19 , Signal Transduction , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/prevention & control , Comorbidity , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Up-Regulation
9.
Therapie ; 75(4): 319-325, 2020.
Article in English | MEDLINE | ID: covidwho-1005554

ABSTRACT

Some concerns about the prescription of drugs acting on the renin-angiotensin system (angiotensin-converting enzyme 1 (ACE1) inhibitors, ACEi; angiotensin II type 1 receptor blockers, ARB) have emerged due to SARS COV2 and COVID-19 pandemic. These very legitimate questions are directly the consequence of the recent recognition of the fundamental role of ACE2 (angiotensin-converting enzyme 2) in COVID-19 infection. Indeed, SARS COV2 utilizes ACE2 as a membrane receptor to enter target cells. Consequently, the putative impact of drugs modulating the renin-angiotensin system on the risk of developing severe or fatal severe acute respiratory syndrome in case of COVID-19 infection emerged. As a membrane-bound enzyme (carboxypeptidase), ACE2 inactivates angiotensin II and therefore physiologically counters its effects. Due to a different structure compared with ACE1, ACE2 is insensitive to ACEIs. In vitro, both ARBs and ACEi appear able to upregulate ACE2 tissue expression and activity but these results were not confirmed in Humans. The exact impact of both ARBs and ACEis on COVID-19 infection is definitively known and preliminary results are even in favor of a protective role confers by these drugs. Due to the crucial role of ACE2, some groups support the hypothesis that a modulation of ACE2 expression could represent a valuable therapeutic target could confer protective properties against inflammatory tissue damage in COVID-19 infection. So, studies are currently ongoing to test the impact of elevated ACE2 membrane expression, administration of ARB and infusion of soluble ACE2. In summary, based on the currently available evidences and as recommended by several medical societies, ACEi or ARB should not be systematically discontinued because to date no safety signal was raised with the use of these drugs.


Subject(s)
Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Renin-Angiotensin System/drug effects , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/virology , Humans , Pandemics , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , SARS-CoV-2
10.
Br J Pharmacol ; 177(21): 4825-4844, 2020 11.
Article in English | MEDLINE | ID: covidwho-998826

ABSTRACT

Angiotensin Converting Enzyme2 is the cell surface binding site for the coronavirus SARS-CoV-2, which causes COVID-19. We propose that an imbalance in the action of ACE1- and ACE2-derived peptides, thereby enhancing angiotensin II (Ang II) signalling is primary driver of COVID-19 pathobiology. ACE1/ACE2 imbalance occurs due to the binding of SARS-CoV-2 to ACE2, reducing ACE2-mediated conversion of Ang II to Ang peptides that counteract pathophysiological effects of ACE1-generated ANG II. This hypothesis suggests several approaches to treat COVID-19 by restoring ACE1/ACE2 balance: (a) AT receptor antagonists; (b) ACE1 inhibitors (ACEIs); (iii) agonists of receptors activated by ACE2-derived peptides (e.g. Ang (1-7), which activates MAS1); (d) recombinant human ACE2 or ACE2 peptides as decoys for the virus. Reducing ACE1/ACE2 imbalance is predicted to blunt COVID-19-associated morbidity and mortality, especially in vulnerable patients. Importantly, approved AT antagonists and ACEIs can be rapidly repurposed to test their efficacy in treating COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Betacoronavirus/enzymology , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Drug Repositioning , Humans , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , SARS-CoV-2
11.
Diabetes ; 70(3): 759-771, 2021 03.
Article in English | MEDLINE | ID: covidwho-976150

ABSTRACT

The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, quantitative RT-PCR, and liquid chromatography-tandem mass spectrometry, we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high-fat diet, and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Diabetes Mellitus, Experimental/metabolism , Diet, High-Fat , Kidney/metabolism , Lung/metabolism , Serine Endopeptidases/genetics , Age Factors , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , COVID-19 , Immunoblotting , In Situ Hybridization , Kidney/drug effects , Lung/drug effects , Male , Mice , Ramipril/pharmacology , Receptors, Coronavirus/drug effects , Receptors, Coronavirus/genetics , Receptors, Coronavirus/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Serine Endopeptidases/drug effects , Serine Endopeptidases/metabolism , Telmisartan/pharmacology
12.
Mol Biol Rep ; 47(12): 9939-9949, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-969167

ABSTRACT

The outbreak of a novel coronavirus namely SARS-CoV-2, which first emerged from Wuhan, China, has wreaked havoc not only in China but the whole world that now has been engulfed in its wrath. In a short lapse of time, this virus was successful in spreading at a blistering pace throughout the globe, hence raising the flag of pandemic status. The mounting number of deaths with each elapsing day has summoned researchers from all around the world to play their part in driving this SARS-CoV-2 pandemic to an end. As of now, multiple research teams are immersed in either scrutinizing various antiviral drugs for their efficacy or developing different types of vaccines that will be capable of providing long-term immunity against this deadly virus. The mini-review sheds light on the possible approaches that can be undertaken to curb the COVID-19 spread. Possible strategies comprise viral vector-based, nucleic acid-based, protein-based, inactivated and weakened virus vaccines; COVID-19 vaccine being developed by deploying Hyleukin-7 technology; plant-based chimeric protein and subunit vaccines; humanized nano-bodies and human antibodies; intravenous immunoglobulin (IVIG) infusion therapy; inhibitors for ACE-2, Angiotensin 1 receptor (AT1R), complement system, viral proteins, host cell protease and endocytosis; shield immunity; IL-6R, NKG2A and hACE2-SARS-CoV-2-RBD interaction blocking monoclonal antibodies; SARS-CoV RdRp-based drugs, traditional Chinese medicine, repositioned and anti-viral drugs. These vaccines and drugs are currently being screened in the clinical trials as several of them have manifested positive results, hence increasing the probability of becoming one of the potential treatments for this disease.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 Vaccines/pharmacology , COVID-19/drug therapy , COVID-19/prevention & control , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antibodies, Monoclonal/pharmacology , Clinical Trials as Topic , Drug Repositioning , Humans , Infectious bronchitis virus/immunology , Mesenchymal Stem Cell Transplantation/methods , RNA, Messenger/immunology , Recombinant Proteins/genetics , Single-Domain Antibodies/pharmacology , Vaccines, Attenuated/pharmacology , Vaccines, Subunit/pharmacology , Vaccines, Synthetic/pharmacology
13.
Cardiovasc Res ; 116(10): 1688-1699, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-889504

ABSTRACT

Systemic arterial hypertension (referred to as hypertension herein) is a major risk factor of mortality worldwide, and its importance is further emphasized in the context of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as COVID-19. Patients with severe COVID-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of COVID-19 in relation to hypertension itself as well as its treatment with renin-angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We provide a critical review on the relationship of hypertension, RAS, and risk of lung injury. We demonstrate lack of sound evidence that hypertension per se is an independent risk factor for COVID-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. We also review in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with COVID-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney, and other tissues. In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in COVID-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the COVID-19 pandemic.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Lung Injury/complications , Pneumonia, Viral/drug therapy , Respiratory Tract Infections/drug therapy , Angiotensin II Type 1 Receptor Blockers/pharmacology , COVID-19 , Coronavirus Infections/diagnosis , Humans , Lung Injury/drug therapy , Lung Injury/virology , Pandemics , Pneumonia, Viral/diagnosis , Renin-Angiotensin System/drug effects , Respiratory Tract Infections/virology , Risk Factors , SARS-CoV-2
14.
Biomed Pharmacother ; 131: 110653, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-722385

ABSTRACT

BACKGROUND: Angiotensin receptor blockers (ARBs) reducing inflammation and protecting lung and brain function, could be of therapeutic efficacy in COVID-19 patients. METHODS: Using GSEA, we compared our previous transcriptome analysis of neurons injured by glutamate and treated with the ARB Candesartan (GSE67036) with transcriptional signatures from SARS-CoV-2 infected primary human bronchial epithelial cells (NHBE) and lung postmortem (GSE147507), PBMC and BALF samples (CRA002390) from COVID-19 patients. RESULTS: Hundreds of genes upregulated in SARS-CoV-2/COVID-19 transcriptomes were similarly upregulated by glutamate and normalized by Candesartan. Gene Ontology analysis revealed expression profiles with greatest significance and enrichment, including proinflammatory cytokine and chemokine activity, the NF-kappa B complex, alterations in innate and adaptive immunity, with many genes participating in the COVID-19 cytokine storm. CONCLUSIONS: There are similar injury mechanisms in SARS-CoV-2 infection and neuronal injury, equally reduced by ARB treatment. This supports the hypothesis of a therapeutic role for ARBs, ameliorating the COVID-19 cytokine storm.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Benzimidazoles/pharmacology , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Pneumonia, Viral/drug therapy , Tetrazoles/pharmacology , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Biphenyl Compounds , Bronchi/cytology , Bronchoalveolar Lavage Fluid/virology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Cytokine Release Syndrome/virology , Epithelial Cells/drug effects , Epithelial Cells/virology , Gene Expression Profiling , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2 , Transcriptome
15.
Int J Cardiol ; 321: 150-154, 2020 12 15.
Article in English | MEDLINE | ID: covidwho-689119

ABSTRACT

A role for the renin-angiotensin-aldosterone-system in Severe Acute Respiratory Syndrome-Coronavirus-2 infection and in the development of COronaVIrus Disease-19 disease has generated remarkable concerns among physicians and patients. Even though a suggestive pathophysiological link between renin-angiotensin-aldosterone-system and the virus has been proposed, its pathogenic role remains very difficult to be defined. Although COronaVIrus Disease-19 targets preferentially older people with high prevalence of hypertension and extensive use of renin-angiotensin-aldosterone-system inhibitors, an independent role for hypertension and its therapies is not defined. In this article, we scrutinize evidence from the most representative available studies in which the potential role of renin-angiotensin system inhibitors, specifically angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, was evaluated in the COronaVIrus Disease-19 disease course, with regard to severity of the disease and mortality. We conclude that at this time, the overall available evidence fails to support a pathogenetic speaks against any harmful role for of renin-angiotensin-aldosterone-system inhibitors in COronaVIrus Disease-19. Consequently, we conclude that treatment with renin-angiotensin-aldosterone-system inhibitors should not be discontinued and, therefore, these therapies should not be interrupted.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Betacoronavirus/physiology , Coronavirus Infections , Hypertension/drug therapy , Pandemics , Pneumonia, Viral , Renin-Angiotensin System , COVID-19 , Coronavirus Infections/metabolism , Coronavirus Infections/physiopathology , Humans , Pneumonia, Viral/metabolism , Pneumonia, Viral/physiopathology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2
17.
Clin Appl Thromb Hemost ; 26: 1076029620936776, 2020.
Article in English | MEDLINE | ID: covidwho-657787

ABSTRACT

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/complications , Pandemics , Pneumonia, Viral/complications , Thrombophilia/etiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anticoagulants/therapeutic use , Arterial Occlusive Diseases/etiology , Arterial Occlusive Diseases/physiopathology , Arterial Occlusive Diseases/virology , COVID-19 , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Catheterization, Swan-Ganz , Combined Modality Therapy , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Endothelium, Vascular/physiopathology , Endothelium, Vascular/virology , Fibrinolytic Agents/therapeutic use , Humans , Hyperbaric Oxygenation , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pulmonary Embolism/etiology , Pulmonary Embolism/therapy , Pulmonary Embolism/virology , Respiratory Distress Syndrome/etiology , SARS-CoV-2 , Thrombolytic Therapy/instrumentation , Thrombolytic Therapy/methods , Thrombophilia/physiopathology , Thrombophilia/therapy , Venous Thrombosis/etiology , Venous Thrombosis/physiopathology , Venous Thrombosis/virology , Virus Internalization/drug effects
18.
Am J Med Sci ; 360(4): 338-341, 2020 10.
Article in English | MEDLINE | ID: covidwho-650676

ABSTRACT

Severe Acute Respiratory Distress Syndrome caused by a novel human coronavirus SARS-CoV-2 named COVID-19 and declared as a pandemic. This paper reviews the possibility of repurposing angiotensin type 1 receptor (AT1R) antagonists and vitamin D to treat COVID-19. ACE2 protein found on the cell membranes is the target of SARS-CoV-2 for entering into the host cells. Viral spike protein-binding with ACE2 down-regulates it. As ACE2 is known to protect the lung from injuries, SARS-CoV-2-induced ACE2 deficiency may expose patients to lung damage. AT1R antagonists and vitamin D increase the expression of ACE2 independently. Besides, vitamin D suppresses the compensatory increase in renin levels following the inhibition of the renin-angiotensin system by AT1R antagonists. Therefore, a combination of AT1R antagonists and vitamin D may offer protection against COVID-19 induced lung injury.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Vitamin D/therapeutic use , Vitamins/therapeutic use , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/complications , Host-Pathogen Interactions , Humans , Pandemics , Peptidyl-Dipeptidase A/blood , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Renin-Angiotensin System/drug effects , SARS-CoV-2 , Severe Acute Respiratory Syndrome/virology , Virus Internalization , Vitamin D/pharmacology , Vitamins/pharmacology
19.
J Physiol Pharmacol ; 71(2)2020 Apr.
Article in English | MEDLINE | ID: covidwho-635661

ABSTRACT

COVID-19, which is caused by the single-stranded RNA severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has introduced significant therapeutic dilemmas in several areas. One of these is concern regarding the use of renin-angiotensin system (RAS) inhibitors. Dysfunction of the RAS has been observed in COVID-19 patients, but whether RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs), are associated with improved or worse clinical outcomes, remains unclear. RAS inhibitors are currently widely used in the treatment of hypertension. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with co-morbidities such as hypertension, coronary heart disease, and diabetes mellitus, particularly in the elderly. Therefore, several recently published research papers have focused on the management of hypertension during the COVID-19 pandemic, as this co-morbidity was found to be the most common in patients with coronavirus infections. SARS-CoV-2 viral surface protein is known to attach angiotensin converting enzyme-2 (ACE-2) on the cell membrane to facilitate viral entry into the cytoplasm. While the SARS-CoV-2 viral load remains the highest in upper respiratory tract of COVID-19 patients, it has also been reported in multiple sites in COVID-19, and patients not infrequently require the Intensive Care Units (ICU) admission. However, despite the theoretical concerns of possible increased ACE2 expression by RAS blockade, there is no evidence that RAS inhibitors are harmful during COVID-19 infection, and indeed they have been shown to be beneficial in some animal studies. In this review we summarise the pathophysiology of the interaction between RAS, ACEIs/ARBs inhibitors and COVID-19, and conclude, on the basis of current data, that RAS blockade should be maintained during the current coronavirus pandemic.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Angiotensin II Type 1 Receptor Blockers/adverse effects , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/virology , Humans , Hypertension/drug therapy , Pandemics , Pneumonia, Viral/virology , Renin-Angiotensin System/drug effects , SARS-CoV-2
20.
Hipertens Riesgo Vasc ; 37(4): 176-180, 2020.
Article in Spanish | MEDLINE | ID: covidwho-615690

ABSTRACT

The association between hypertension, diabetes, cardio and cerebrovascular disease and severe and fatal COVID-19, described in different countries, is remarkable. Myocardial damage and myocardial dysfunction are postulated as a possible causal nexus. Frequent findings of elevated troponin levels and electrocardiographic anomalies support this concept. On the other hand, hypotheses in favour and against a deleterious effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers, a usual treatment for cardiovascular disease, have been raised. There is currently no solid evidence and thus properly designed studies on this subject are urgently needed. In this context, patients with cardiovascular disease should especially avoid being exposed to the virus, should not self-medicate and rapidly seek medical advice should they show symptoms of infection.


Subject(s)
Betacoronavirus , Cardiovascular Diseases/physiopathology , Coronavirus Infections/physiopathology , Pandemics , Pneumonia, Viral/physiopathology , Age Factors , Aged , Angiotensin II Type 1 Receptor Blockers/adverse effects , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Cardiovascular Diseases/complications , Coronavirus Infections/complications , Early Diagnosis , Heart/physiopathology , Humans , Hypertension/complications , Hypertension/drug therapy , Hypertension/physiopathology , Middle Aged , Myocarditis/etiology , Myocarditis/physiopathology , Peptidyl-Dipeptidase A/drug effects , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/complications , Receptors, Virus/drug effects , Receptors, Virus/physiology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , Risk Factors , SARS-CoV-2 , Self Medication
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