|
1
|
Lima EBDS, Carvalho AFS, Zaidan I, Monteiro AHA, Cardoso C, Lara ES, Carneiro FS, Oliveira LC, Resende F, Santos FRDS, Souza-Costa LP, Chaves IDM, Queiroz-Junior CM, Russo RC, Santos RAS, Tavares LP, Teixeira MM, Costa VV, Sousa LP. Angiotensin-(1-7) decreases inflammation and lung damage caused by betacoronavirus infection in mice. Inflamm Res 2024; 73:2009-2022. [PMID: 39292270 DOI: 10.1007/s00011-024-01948-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 09/19/2024] Open
Abstract
OBJECTIVE Pro-resolving molecules, including the peptide Angiotensin-(1-7) [Ang-(1-7)], have potential adjunctive therapy for infections. Here we evaluate the actions of Ang-(1-7) in betacoronavirus infection in mice. METHODS C57BL/6J mice were infected intranasally with the murine betacoronavirus MHV-3 and K18-hACE2 mice were infected with SARS-CoV-2. Mice were treated with Ang-(1-7) (30 µg/mouse, i.p.) at 24-, 36-, and 48-hours post-infection (hpi) or at 24, 36, 48, 72, and 96 h. For lethality evaluation, one additional dose of Ang-(1-7) was given at 120 hpi. At 3- and 5-days post- infection (dpi) blood cells, inflammatory mediators, viral loads, and lung histopathology were evaluated. RESULTS Ang-(1-7) rescued lymphopenia in MHV-infected mice, and decreased airways leukocyte infiltration and lung damage at 3- and 5-dpi. The levels of pro-inflammatory cytokines and virus titers in lung and plasma were decreased by Ang-(1-7) during MHV infection. Ang-(1-7) improved lung function and increased survival rates in MHV-infected mice. Notably, Ang-(1-7) treatment during SARS-CoV-2 infection restored blood lymphocytes to baseline, decreased weight loss, virus titters and levels of inflammatory cytokines, resulting in improvement of pulmonary damage, clinical scores and lethality rates. CONCLUSION Ang-(1-7) protected mice from lung damage and death during betacoronavirus infections by modulating inflammation, hematological parameters and enhancing viral clearance.
Collapse
Affiliation(s)
- Erick Bryan de Sousa Lima
- Programa de Pós-graduação em Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, 31270-901, Brazil
- Hospital das Clínicas da Universidade Federal de Minas Gerais/Ebserh, Belo Horizonte, Minas Gerais, Brazil
| | - Antônio Felipe S Carvalho
- Programa de Pós-graduação em Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, 31270-901, Brazil
- Hospital das Clínicas da Universidade Federal de Minas Gerais/Ebserh, Belo Horizonte, Minas Gerais, Brazil
| | - Isabella Zaidan
- Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Adelson Héric A Monteiro
- Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Camila Cardoso
- Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Edvaldo S Lara
- Programa de Pós-graduação em Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, 31270-901, Brazil
| | - Fernanda S Carneiro
- Programa de Pós-graduação em Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, 31270-901, Brazil
| | - Leonardo C Oliveira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Filipe Resende
- Programa de Pós-graduação em Biologia Celular, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Felipe Rocha da Silva Santos
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luiz Pedro Souza-Costa
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ian de Meira Chaves
- Programa de Pós-graduação em Biologia Celular, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Celso M Queiroz-Junior
- Programa de Pós-graduação em Biologia Celular, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Remo C Russo
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Robson A S Santos
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, National Institute in Science and Technology in nanobiopharmaceutics, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luciana P Tavares
- Department of Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Mauro M Teixeira
- Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vivian V Costa
- Programa de Pós-graduação em Biologia Celular, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Lirlândia P Sousa
- Programa de Pós-graduação em Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, 31270-901, Brazil.
- Programa de Pós-graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
| |
Collapse
|
|
2
|
Prato M, Tiberti N, Mazzi C, Gobbi F, Piubelli C, Longoni SS. The Renin-Angiotensin System (RAS) in COVID-19 Disease: Where We Are 3 Years after the Beginning of the Pandemic. Microorganisms 2024; 12:583. [PMID: 38543635 PMCID: PMC10975343 DOI: 10.3390/microorganisms12030583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/04/2024] [Accepted: 03/08/2024] [Indexed: 11/12/2024] Open
Abstract
The RAS is a hormonal system playing a pivotal role in the control of blood pressure and electrolyte homeostasis, the alteration of which is associated with different pathologies, including acute respiratory distress syndrome (ARDS). As such, it is not surprising that a number of studies have attempted to elucidate the role and balance of the renin-angiotensin system (RAS) in COVID-19. In this review article, we will describe the evidence collected regarding the two main enzymes of the RAS (i.e., ACE and ACE2) and their principal molecular products (i.e., AngII and Ang1-7) in SARS-CoV-2 infection, with the overarching goal of drawing conclusions on their possible role as clinical markers in association with disease severity, progression, and outcome. Moreover, we will bring into the picture new experimental data regarding the systemic activity of ACE and ACE2 as well as the concentration of AngII and Ang1-7 in a cohort of 47 COVID-19 patients hospitalized at the IRCCS Sacro Cuore-Don Calabria Hospital (Negrar, Italy) between March and April 2020. Finally, we will discuss the possibility of considering this systemic pathway as a clinical marker for COVID-19.
Collapse
Affiliation(s)
- Marco Prato
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy
| | - Natalia Tiberti
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy
| | - Cristina Mazzi
- Centre for Clinical Research, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy
| | - Federico Gobbi
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy
| | - Chiara Piubelli
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy
| | - Silvia Stefania Longoni
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Negrar di Valpolicella, 37024 Verona, Italy
| |
Collapse
|
|
3
|
Holmes D, Colaneri M, Palomba E, Gori A. Exploring post-SEPSIS and post-COVID-19 syndromes: crossovers from pathophysiology to therapeutic approach. Front Med (Lausanne) 2024; 10:1280951. [PMID: 38249978 PMCID: PMC10797045 DOI: 10.3389/fmed.2023.1280951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/07/2023] [Indexed: 01/23/2024] Open
Abstract
Sepsis, driven by several infections, including COVID-19, can lead to post-sepsis syndrome (PSS) and post-acute sequelae of COVID-19 (PASC). Both these conditions share clinical and pathophysiological similarities, as survivors face persistent multi-organ dysfunctions, including respiratory, cardiovascular, renal, and neurological issues. Moreover, dysregulated immune responses, immunosuppression, and hyperinflammation contribute to these conditions. The lack of clear definitions and diagnostic criteria hampers comprehensive treatment strategies, and a unified therapeutic approach is significantly needed. One potential target might be the renin-angiotensin system (RAS), which plays a significant role in immune modulation. In fact, RAS imbalance can exacerbate these responses. Potential interventions involving RAS include ACE inhibitors, ACE receptor blockers, and recombinant human ACE2 (rhACE2). To address the complexities of PSS and PASC, a multifaceted approach is required, considering shared immunological mechanisms and the role of RAS. Standardization, research funding, and clinical trials are essential for advancing treatment strategies for these conditions.
Collapse
Affiliation(s)
- Darcy Holmes
- Infectious Diseases Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marta Colaneri
- Department of Infectious Diseases, Luigi Sacco Hospital, Milan, Italy
| | - Emanuele Palomba
- Department of Infectious Diseases, Luigi Sacco Hospital, Milan, Italy
| | - Andrea Gori
- Department of Infectious Diseases, Luigi Sacco Hospital, Milan, Italy
- Centre for Multidisciplinary Research in Health Science (MACH), University of Milan, Milan, Italy
| |
Collapse
|
|
4
|
Omidkhah N, Hadizadeh F, Ghodsi R, Kesharwani P, Sahebkar A. In silico Evaluation of NO-Sartans against SARS-CoV-2. Curr Drug Discov Technol 2024; 21:e050324227669. [PMID: 38445698 DOI: 10.2174/0115701638279362240223070810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/16/2024] [Accepted: 01/29/2024] [Indexed: 03/07/2024]
Abstract
INTRODUCTION Numerous clinical trials are currently investigating the potential of nitric oxide (NO) as an antiviral agent against coronaviruses, including SARS-CoV-2. Additionally, some researchers have reported positive effects of certain Sartans against SARS-CoV-2. METHOD Considering the impact of NO-Sartans on the cardiovascular system, we have compiled information on the general structure, synthesis methods, and biological studies of synthesized NOSartans. In silico evaluation of all NO-Sartans and approved sartans against three key SARS-CoV- -2 targets, namely Mpro (PDB ID: 6LU7), NSP16 (PDB ID: 6WKQ), and ACE-2 (PDB ID: 1R4L), was performed using MOE. RESULTS Almost all NO-Sartans and approved sartans demonstrated promising results in inhibiting these SARS-CoV-2 targets. Compound 36 (CLC-1280) showed the best docking scores against the three evaluated targets and was further evaluated using molecular dynamics (MD) simulations. CONCLUSION Based on our in silico studies, CLC-1280 (a Valsartan dinitrate) has the potential to be considered as an inhibitor of the SARS-CoV-2 virus. However, further in vitro and in vivo evaluations are necessary for the drug development process.
Collapse
Affiliation(s)
- Negar Omidkhah
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzin Hadizadeh
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Razieh Ghodsi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard University, New Delhi, 110062, India
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
5
|
Ghimire B, Pour SK, Middleton E, Campbell RA, Nies MA, Aghazadeh-Habashi A. Renin-Angiotensin System Components and Arachidonic Acid Metabolites as Biomarkers of COVID-19. Biomedicines 2023; 11:2118. [PMID: 37626615 PMCID: PMC10452267 DOI: 10.3390/biomedicines11082118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Through the ACE2, a main enzyme of the renin-angiotensin system (RAS), SARS-CoV-2 gains access into the cell, resulting in different complications which may extend beyond the RAS and impact the Arachidonic Acid (ArA) pathway. The contribution of the RAS through ArA pathways metabolites in the pathogenesis of COVID-19 is unknown. We investigated whether RAS components and ArA metabolites can be considered biomarkers of COVID-19. We measured the plasma levels of RAS and ArA metabolites using an LC-MS/MS. Results indicate that Ang 1-7 levels were significantly lower, whereas Ang II levels were higher in the COVID-19 patients than in healthy control individuals. The ratio of Ang 1-7/Ang II as an indicator of the RAS classical and protective arms balance was dramatically lower in COVID-19 patients. There was no significant increase in inflammatory 19-HETE and 20-HETE levels. The concentration of EETs was significantly increased in COVID-19 patients, whereas the DHETs concentration was repressed. Their plasma levels were correlated with Ang II concentration in COVID-19 patients. In conclusion, evaluating the RAS and ArA pathway biomarkers could provide helpful information for the early detection of high-risk groups, avoid delayed medical attention, facilitate resource allocation, and improve patient clinical outcomes to prevent long COVID incidence.
Collapse
Affiliation(s)
- Biwash Ghimire
- College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA; (B.G.)
| | - Sana Khajeh Pour
- College of Pharmacy, Idaho State University, Pocatello, ID 83209, USA; (B.G.)
| | - Elizabeth Middleton
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT 84112, USA
| | - Robert A. Campbell
- Department of Internal Medicine, Division ofHematology, University of Utah, Salt Lake City, UT 84112, USA
| | - Mary A. Nies
- College of Health, School of Nursing, Idaho State University, Pocatello, ID 83209, USA
| | | |
Collapse
|
|
6
|
Murali R, Wanjari UR, Mukherjee AG, Gopalakrishnan AV, Kannampuzha S, Namachivayam A, Madhyastha H, Renu K, Ganesan R. Crosstalk between COVID-19 Infection and Kidney Diseases: A Review on the Metabolomic Approaches. Vaccines (Basel) 2023; 11:vaccines11020489. [PMID: 36851366 PMCID: PMC9959335 DOI: 10.3390/vaccines11020489] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory disorder. Various organ injuries have been reported in response to this virus, including kidney injury and, in particular, kidney tubular injury. It has been discovered that infection with the virus does not only cause new kidney disease but also increases treatment difficulty and mortality rates in people with kidney diseases. In individuals hospitalized with COVID-19, urinary metabolites from several metabolic pathways are used to distinguish between patients with acute kidney injury (AKI) and those without. This review summarizes the pathogenesis, pathophysiology, treatment strategies, and role of metabolomics in relation to AKI in COVID-19 patients. Metabolomics is likely to play a greater role in predicting outcomes for patients with kidney disease and COVID-19 with varying levels of severity in the near future as data on metabolic profiles expand rapidly. Here, we also discuss the correlation between COVID-19 and kidney diseases and the available metabolomics approaches.
Collapse
Affiliation(s)
- Reshma Murali
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
- Correspondence: (A.V.G.); (R.G.)
| | - Sandra Kannampuzha
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Arunraj Namachivayam
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, Tamil Nadu, India
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan
| | - Kaviyarasi Renu
- Center of Molecular Medicine and Diagnostics (COMMAND), Department of Biochemistry, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, Tamil Nadu, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
- Correspondence: (A.V.G.); (R.G.)
| |
Collapse
|
|
7
|
Lung Injury in COVID-19 Has Pulmonary Edema as an Important Component and Treatment with Furosemide and Negative Fluid Balance (NEGBAL) Decreases Mortality. J Clin Med 2023; 12:jcm12041542. [PMID: 36836076 PMCID: PMC9966668 DOI: 10.3390/jcm12041542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/09/2023] [Accepted: 02/11/2023] [Indexed: 02/18/2023] Open
Abstract
The SARS-CoV2 promotes dysregulation of Renin-Angiotensin-Aldosterone. The result is excessive retention of water, producing a state of noxious hypervolemia. Consequently, in COVID-19 injury lung is pulmonary edema. Our report is a case-control study, retrospective. We included 116 patients with moderate-severe COVID-19 lung injury. A total of 58 patients received standard care (Control group). A total of 58 patients received a standard treatment with a more negative fluid balance (NEGBAL group), consisting of hydric restriction and diuretics. Analyzing the mortality of the population studied, it was observed that the NEGBAL group had lower mortality than the Control group, p = 0.001. Compared with Controls, the NEGBAL group had significantly fewer days of hospital stay (p < 0.001), fewer days of ICU stay (p < 0.001), and fewer days of IMV (p < 0.001). The regressive analysis between PaO2/FiO2BAL and NEGBAL demonstrated correlation (p = 0.04). Compared with Controls, the NEGBAL group showed significant progressive improvement in PaO2/FiO2 (p < 0.001), CT score (p < 0.001). The multivariate model, the vaccination variables, and linear trends resulted in p = 0.671 and quadratic trends p = 0.723, whilst the accumulated fluid balance is p < 0.001. Although the study has limitations, the promising results encourage more research on this different therapeutic approach, since in our research it decreases mortality.
Collapse
|
|
8
|
Aleksova A, Fluca AL, Gagno G, Pierri A, Padoan L, Derin A, Moretti R, Noveska EA, Azzalini E, D'Errico S, Beltrami AP, Zumla A, Ippolito G, Sinagra G, Janjusevic M. Long-term effect of SARS-CoV-2 infection on cardiovascular outcomes and all-cause mortality. Life Sci 2022; 310:121018. [PMID: 36183780 PMCID: PMC9561478 DOI: 10.1016/j.lfs.2022.121018] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/19/2022] [Accepted: 09/27/2022] [Indexed: 12/03/2022]
Abstract
Since the very beginning of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, it was evident that patients with cardiovascular disease (CVD) were at an increased risk of developing severe illness, and complications spanning cerebrovascular disorders, dysrhythmias, acute coronary syndrome, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, thromboembolic disease, stroke, and death. Underlying these was excessive systemic inflammation and coagulopathy due to SARS-COV-2 infection, the effects of which also continued long-term as evidenced by post-COVID-19 cardiovascular complications. The acute and chronic cardiovascular effects of COVID-19 occurred even among those who were not hospitalized and had no previous CVD or those with mild symptoms. This comprehensive review summarizes the current understanding of molecular mechanisms triggered by the SARS-CoV-2 virus on various cells that express the angiotensin-converting enzyme 2, leading to endothelial dysfunction, inflammation, myocarditis, impaired coagulation, myocardial infarction, arrhythmia and a multisystem inflammatory syndrome in children or Kawasaki-like disease.
Collapse
Affiliation(s)
- Aneta Aleksova
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy.
| | - Alessandra Lucia Fluca
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Giulia Gagno
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Alessandro Pierri
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Laura Padoan
- Department of Cardiology and Cardiovascular Physiopathology, Università degli Studi di Perugia, Perugia, Italy
| | - Agnese Derin
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy
| | - Rita Moretti
- Department of Internal Medicine and Neurology, Neurological Clinic, University of Trieste, Trieste, Italy
| | - Elena Aleksova Noveska
- Department of Pediatric and Preventive Dentistry, Faculty of Dental Medicine, Ss. Cyril and Methodius University, Skopje, Macedonia
| | - Eros Azzalini
- Department of Medical Sciences (DSM), University of Trieste, Trieste, Italy
| | - Stefano D'Errico
- Department of Medicine, Surgery and Health, University of Trieste, Trieste, Italy
| | | | - Alimuddin Zumla
- Department of Infection, Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, London, UK; National Institute for Health Research Biomedical Research Centre, University College London Hospitals, London, UK
| | | | - Gianfranco Sinagra
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Milijana Janjusevic
- Azienda Sanitaria Universitaria Giuliano Isontina, Cardiothoracovascular Department, Trieste, Italy; Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy
| |
Collapse
|
|
9
|
Abstract
The coronavirus SARS-CoV-2 infects host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which belongs to an anti-inflammatory, anti-thrombotic counter-regulatory arm of the renin-angiotensin system (RAS). ACE2 dysfunction and RAS dysregulation has been explored as a driving force in acute respiratory distress syndrome (ARDS), but data from COVID-19 patients has been inconsistent and inconclusive. We sought to identify disruptions of the classical (ACE)/angiotensin (Ang) II/Ang II type-1 receptor (AT1R) and the counter-regulatory ACE2/Ang 1-7/Mas Receptor (MasR) pathways in patients with COVID-19 and correlate these with severity of infection and markers of inflammation and coagulation. Ang II and Ang 1–7 levels in plasma were measured by enzyme-linked immunosorbent assay (ELISA) for 230 patients, 166 of whom were SARS-CoV-2+. Ang 1–7 was repressed in COVID-19 patients compared to that in SARS-CoV-2 negative outpatient controls. Since the control cohort was less sick than the SARS-CoV-2+ group, this association between decreased Ang 1–7 and COVID-19 cannot be attributed to COVID-19 specifically as opposed to critical illness more generally. Multivariable logistic regression analyses demonstrated that every 10-pg/mL increase in plasma Ang 1–7 was associated with a 3% reduction in the odds of hospitalization (adjusted odds ratio [AOR] 0.97, confidence interval [CI] 0.95 to 0.99) and a 3% reduction in odds of requiring oxygen supplementation (AOR 0.97, CI 0.95 to 0.99) and/or ventilation (AOR 0.97, CI 0.94 to 0.99). Ang 1–7 was also inversely associated with pro-inflammatory cytokines and d-dimer in this patient cohort, suggesting that reduced activity in this protective counter-regulatory arm of the RAS contributes to the hyper-immune response and diffuse coagulation activation documented in COVID-19. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a unique disease, COVID-19, which ranges in severity from asymptomatic to causing severe respiratory failure and death. Viral transmission throughout the world continues at a high rate despite the development and widespread use of effective vaccines. For those patients who contract COVID-19 and become severely ill, few therapeutic options have been shown to provide benefits and mortality rates are high. Additionally, the pathophysiology underlying COVID-19 disease presentation, progression, and severity is incompletely understood. The significance of our research is in confirming the role of renin-angiotensin system dysfunction in COVID-19 pathogenesis in a large cohort of patients with diverse disease severity and outcomes. Additionally, to our knowledge, this is the first study to pair angiotensin peptide levels with inflammatory and thrombotic markers. These data support the role of ongoing clinical trials examining renin-angiotensin system-targeted therapeutics for the treatment of COVID-19.
Collapse
|
|
10
|
Silva MG, Corradi GR, Pérez Duhalde JI, Nuñez M, Cela EM, Gonzales Maglio DH, Brizzio A, Salazar MR, Espeche WG, Gironacci MM. Plasmatic renin-angiotensin system in normotensive and hypertensive patients hospitalized with COVID-19. Biomed Pharmacother 2022; 152:113201. [PMID: 35661534 PMCID: PMC9135678 DOI: 10.1016/j.biopha.2022.113201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 11/19/2022] Open
Abstract
Background Besides its counterbalancing role of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) 2 is the receptor for the type 2 coronavirus that causes severe acute respiratory syndrome, the etiological agent of COVID-19. COVID-19 is associated with increased plasmatic ACE2 levels, although conflicting results have been reported regarding angiotensin (Ang) II and Ang-(1−7) levels. We investigated plasmatic ACE2 protein levels and enzymatic activity and Ang II and Ang-(1−7) levels in normotensive and hypertensive patients hospitalized with COVID-19 compared to healthy subjects. Methods Ang II and Ang-(1−7), and ACE2 activity and protein levels were measured in 93 adults (58 % (n = 54) normotensive and 42 % (n = 39) hypertensive) hospitalized with COVID-19. Healthy, normotensive (n = 33) and hypertensive (n = 7) outpatient adults comprised the control group. Results COVID-19 patients displayed higher ACE2 enzymatic activity and protein levels than healthy subjects. Within the COVID-19 group, ACE2 activity and protein levels were not different between normotensive and hypertensive-treated patients, not even between COVID-19 hypertensive patients under RAS blockade treatment and those treated with other antihypertensive medications. Ang II and Ang-(1−7) levels significantly decreased in COVID-19 patients. When COVID-19 patients under RAS blockade treatment were excluded from the analysis, ACE2 activity and protein levels remained higher and Ang II and Ang-(1−7) levels lower in COVID-19 patients compared to healthy people. Conclusions Our results support the involvement of RAS in COVID-19, even when patients under RAS blockade treatment were excluded. The increased circulating ACE2 suggest higher ACE2 expression and shedding.
Collapse
Affiliation(s)
- Mauro G Silva
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina
| | - Gerardo R Corradi
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina
| | - Juan I Pérez Duhalde
- Unidad de Enfermedades Cardiometabólicas, Hospital San Martín de La Plata, La Plata, Argentina
| | - Myriam Nuñez
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Matemáticas, Buenos Aires, Argentina
| | - Eliana M Cela
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Inmunología-IDEHU, Buenos Aires, Argentina
| | - Daniel H Gonzales Maglio
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Inmunología-IDEHU, Buenos Aires, Argentina
| | - Ana Brizzio
- Unidad de Enfermedades Cardiometabólicas, Hospital San Martín de La Plata, La Plata, Argentina
| | - Martin R Salazar
- Unidad de Enfermedades Cardiometabólicas, Hospital San Martín de La Plata, La Plata, Argentina
| | - Walter G Espeche
- Unidad de Enfermedades Cardiometabólicas, Hospital San Martín de La Plata, La Plata, Argentina
| | - Mariela M Gironacci
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina.
| |
Collapse
|
|
11
|
Kassif Lerner R, Stein Yeshurun M, Hemi R, Zada N, Asraf K, Doolman R, Benoit SW, Santos de Oliveira MH, Lippi G, Henry BM, Pessach IM, Pode Shakked N. The Predictive Value of Serum ACE2 and TMPRSS2 Concentrations in Patients with COVID-19-A Prospective Pilot Study. J Pers Med 2022; 12:jpm12040622. [PMID: 35455738 PMCID: PMC9032089 DOI: 10.3390/jpm12040622] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 01/08/2023] Open
Abstract
One of the major challenges for healthcare systems during the Coronavirus-2019 (COVID-19) pandemic was the inability to successfully predict which patients would require mechanical ventilation (MV). Angiotensin-Converting Enzyme 2 (ACE2) and TransMembrane Protease Serine S1 member 2 (TMPRSS2) are enzymes that play crucial roles in SARS-CoV-2 entry into human host cells. However, their predictive value as biomarkers for risk stratification for respiratory deterioration requiring MV has not yet been evaluated. We aimed to evaluate whether serum ACE2 and TMPRSS2 levels are associated with adverse outcomes in COVID-19, and specifically the need for MV. COVID-19 patients admitted to an Israeli tertiary medical center between March--November 2020, were included. Serum samples were obtained shortly after admission (day 0) and again following one week of admission (day 7). ACE2 and TMPRSS2 concentrations were measured with ELISA. Of 72 patients included, 30 (41.6%) ultimately required MV. Serum ACE2 concentrations >7.8 ng/mL at admission were significantly associated with the need for MV (p = 0.036), inotropic support, and renal replacement therapy. In multivariate logistic regression analysis, elevated ACE2 at admission was associated with the need for MV (OR = 7.49; p = 0.014). To conclude, elevated serum ACE2 concentration early in COVID-19 illness correlates with respiratory failure necessitating mechanical ventilation. We suggest that measuring serum ACE2 at admission may be useful for predicting the risk of severe disease.
Collapse
Affiliation(s)
- Reut Kassif Lerner
- Department of Pediatric Intensive Care, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; (R.K.L.); (I.M.P.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; (M.S.Y.); (R.H.); (R.D.)
| | - Michal Stein Yeshurun
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; (M.S.Y.); (R.H.); (R.D.)
- Department of Pediatrics, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel
| | - Rina Hemi
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; (M.S.Y.); (R.H.); (R.D.)
- Division of Endocrinology and Metabolism, Sheba Medical Center, Tel Hashomer 52621, Israel;
| | - Nahid Zada
- Division of Endocrinology and Metabolism, Sheba Medical Center, Tel Hashomer 52621, Israel;
| | - Keren Asraf
- The Dworman Automated-Mega Laboratory, Sheba Medical Center, Tel Hashomer 52621, Israel;
| | - Ram Doolman
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; (M.S.Y.); (R.H.); (R.D.)
- The Dworman Automated-Mega Laboratory, Sheba Medical Center, Tel Hashomer 52621, Israel;
| | - Stefanie W. Benoit
- Division of Pediatric Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (S.W.B.); (B.M.H.)
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | | | - Giuseppe Lippi
- Section of Clinical Biochemistry, University of Verona, 37134 Verona, Italy;
| | - Brandon Michael Henry
- Division of Pediatric Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (S.W.B.); (B.M.H.)
| | - Itai M. Pessach
- Department of Pediatric Intensive Care, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; (R.K.L.); (I.M.P.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; (M.S.Y.); (R.H.); (R.D.)
| | - Naomi Pode Shakked
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel; (M.S.Y.); (R.H.); (R.D.)
- Department of Pediatrics, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel
- Division of Pediatric Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; (S.W.B.); (B.M.H.)
- Correspondence:
| |
Collapse
|
|
12
|
Cook JR, Ausiello J. Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19. Rev Endocr Metab Disord 2022; 23:151-170. [PMID: 34195965 PMCID: PMC8245275 DOI: 10.1007/s11154-021-09663-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/04/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1-7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction.
Collapse
Affiliation(s)
- Joshua R Cook
- New York-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA
| | - John Ausiello
- New York-Presbyterian Hospital and the Columbia University Irving Medical Center, New York, NY, USA.
| |
Collapse
|
|
13
|
Zhang Q, Ling S, Hu K, Liu J, Xu JW. Role of the renin-angiotensin system in NETosis in the coronavirus disease 2019 (COVID-19). Pharmacotherapy 2022; 148:112718. [PMID: 35176710 PMCID: PMC8841219 DOI: 10.1016/j.biopha.2022.112718] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 12/20/2022]
Abstract
Myocardial infarction and stroke are the leading causes of death in the world. Numerous evidence has confirmed that hypertension promotes thrombosis and induces myocardial infarction and stroke. Recent findings reveal that neutrophil extracellular traps (NETs) are involved in the induction of myocardial infarction and stroke. Meanwhile, patients with severe COVID-19 suffer from complications such as myocardial infarction and stroke with pathological signs of NETs. Due to the extremely low amount of virus detected in the blood and remote organs (e.g., heart, brain and kidney) in a few cases, it is difficult to explain the mechanism by which the virus triggers NETosis, and there may be a different mechanism than in the lung. A large number of studies have found that the renin-angiotensin system regulates the NETosis at multiple levels in patients with COVID-19, such as endocytosis of SARS-COV-2, abnormal angiotensin II levels, neutrophil activation and procoagulant function at multiple levels, which may contribute to the formation of reticular structure and thrombosis. The treatment of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARBs) and neutrophil recruitment and active antagonists helps to regulate blood pressure and reduce the risk of net and thrombosis. The review will explore the possible role of the angiotensin system in the formation of NETs in severe COVID-19.
Collapse
|
|
14
|
D’Ardes D, Boccatonda A, Cocco G, Fabiani S, Rossi I, Bucci M, Guagnano MT, Schiavone C, Cipollone F. Impaired coagulation, liver dysfunction and COVID-19: Discovering an intriguing relationship. World J Gastroenterol 2022; 28:1102-1112. [PMID: 35431501 PMCID: PMC8985482 DOI: 10.3748/wjg.v28.i11.1102] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 08/09/2021] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is, at present, one of the most relevant global health problems. In the literature hepatic alterations have been described in COVID-19 patients, and they are mainly represented by worsening of underlying chronic liver disease leading to hepatic decompensation and liver failure with higher mortality. Several potential mechanisms used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to cause liver damage have been hypothesized. COVID-19 primary liver injury is less common than secondary liver injury. Most of the available data demonstrate how liver damage in SARS-CoV-2 infection is likely due to systemic inflammation, and it is less likely mediated by a cytopathic effect directed on liver cells. Moreover, liver alterations could be caused by hypoxic injury and drugs (antibiotics and non-steroidal anti-inflammatory drugs, remdesivir, tocilizumab, tofacitinib and dexamethasone). SARS-CoV-2 infection can induce multiple vascular district atherothrombosis by affecting simultaneously cerebral, coronary and peripheral vascular beds. Data in the literature highlight how the virus triggers an exaggerated immune response, which added to the cytopathic effect of the virus can induce endothelial damage and a prothrombotic dysregulation of hemostasis. This leads to a higher incidence of symptomatic and confirmed venous thrombosis and of pulmonary embolisms, especially in central, lobar or segmental pulmonary arteries, in COVID-19. There are currently fewer data for arterial thrombosis, while myocardial injury was identified in 7%-17% of patients hospitalized with SARS-CoV-2 infection and 22%-31% in the intensive care unit setting. Available data also revealed a higher occurrence of stroke and more serious forms of peripheral arterial disease in COVID-19 patients. Hemostasis dysregulation is observed during the COVID-19 course. Lower platelet count, mildly increased prothrombin time and increased D-dimer are typical laboratory features of patients with severe SARS-CoV-2 infection, described as "COVID-19 associated coagulopathy." These alterations are correlated to poor outcomes. Moreover, patients with severe SARS-CoV-2 infection are characterized by high levels of von Willebrand factor with subsequent ADAMTS13 deficiency and impaired fibrinolysis. Platelet hyperreactivity, hypercoagulability and hypofibrinolysis during SARS-CoV-2 infection induce a pathological state named as "immuno-thromboinflammation." Finally, liver dysfunction and coagulopathy are often observed at the same time in patients with COVID-19. The hypothesis that liver dysfunction could be mediated by microvascular thrombosis has been supported by post-mortem findings and extensive vascular portal and sinusoidal thrombosis observation. Other evidence has shown a correlation between coagulation and liver damage in COVID-19, underlined by the transaminase association with coagulopathy, identified through laboratory markers such as prothrombin time, international normalized ratio, fibrinogen, D-dimer, fibrin/fibrinogen degradation products and platelet count. Other possible mechanisms like immunogenesis of COVID-19 damage or massive pericyte activation with consequent vessel wall fibrosis have been suggested.
Collapse
Affiliation(s)
- Damiano D’Ardes
- “Clinica Medica” Institute, Department of Medicine and Aging Sciences, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Andrea Boccatonda
- Unit of Ultrasound, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Giulio Cocco
- Unit of Ultrasound, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Stefano Fabiani
- Unit of Ultrasound, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Ilaria Rossi
- “Clinica Medica” Institute, Department of Medicine and Aging Sciences, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Marco Bucci
- “Clinica Medica” Institute, Department of Medicine and Aging Sciences, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Maria Teresa Guagnano
- “Clinica Medica” Institute, Department of Medicine and Aging Sciences, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Cosima Schiavone
- Unit of Ultrasound, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| | - Francesco Cipollone
- “Clinica Medica” Institute, Department of Medicine and Aging Sciences, “G. D’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
| |
Collapse
|
|
15
|
Onal H, Ergun NU, Arslan B, Topuz S, Semerci SY, Ugurel OM, Topuzogullari M, Kalkan A, Yoldemir SA, Suner N, Kocatas A. Angiotensin (1- 7) peptide replacement therapy with plasma transfusion in COVID-19. Transfus Apher Sci 2022; 61:103418. [PMID: 35305923 PMCID: PMC8917875 DOI: 10.1016/j.transci.2022.103418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/22/2022] [Accepted: 02/27/2022] [Indexed: 11/19/2022]
Abstract
Aim To determine whether convalescent angiotensin (1−7) peptide replacement therapy with plasma (peptide plasma) transfusion can be beneficial in the treatment of critically ill patients with severe coronavirus 2 (SARS-CoV-2) infection. Study design Case series of 9 critically ill patients with laboratory-confirmed COVID-19 who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment. Peptide plasma: Plasma with angiotensin (1−7) content 8–10 times higher than healthy plasma donors was obtained from suitable donors. Peptide plasma transfusion was applied to 9 patients whose clinical status and/or laboratory profile deteriorated and who needed intensive care for 2 days. Results In our COVID-19 cases, favipiravir, low molecular weight heparin treatment, which is included in the treatment protocol of the ministry of health, was started. Nine patients with oxygen saturation of 93% and below despite nasal oxygen support, whose clinical and/or laboratory deteriorated, were identified. The youngest of the cases was 36 years old, and the oldest patient was 85 years old. 6 of the 9 cases had male gender. 3 cases had been smoking for more than 10 years. 4 cases had at least one chronic disease. In all of our cases, SARS CoV2 lung involvement was bilateral and peptide plasma therapy was administered in cases when oxygen saturation was 93% and below despite nasal oxygen support of 5 liters/minute and above, and intensive care was required. Although it was not reflected in the laboratory parameters in the early period, 8 patients whose saturations improved with treatment were discharged without the need for intensive care. However, a similar response was not obtained in one case. Oxygen requirement increased gradually and, he died in intensive care process. An increase of the platelet count was observed in all cases following the peptide plasma treatment. Conclusion In this preliminary case series of 9 critically ill patients with COVID-19, administration of plasma containing angiotensin (1−7) was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.
Collapse
Affiliation(s)
- Hasan Onal
- Department of Pediatric Nutrition and Metabolism Clinics, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey; Chief of Pediatric Nutrition and Metabolism Department, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
| | - Nurcan Ucuncu Ergun
- Department of Pediatric Nutrition and Metabolism Clinics, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey; Department of Pediatrics, Postdoctorate Fellow of Pediatric Nutrition and Metabolism, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
| | - Bengu Arslan
- Department of Pediatric Nutrition and Metabolism Clinics, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey; Department of Pediatrics, Postdoctorate Fellow of Pediatric Nutrition and Metabolism, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
| | - Seyma Topuz
- Department of Pediatric Nutrition and Metabolism Clinics, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey; Department of Pediatric Nutrition and Metabolism, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
| | - Seda Yilmaz Semerci
- Department of Neonatology, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
| | - Osman Mutluhan Ugurel
- Department of Basic Sciences, School of Engineering and Architecture, Altınbas University, Istanbul, Turkey.
| | - Murat Topuzogullari
- Bioengineering Department, Chemistry and Metallurgy Faculty, Yildiz Technical University, Istanbul, Turkey.
| | - Ali Kalkan
- Department of Cardiology, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey
| | - Sengul Aydin Yoldemir
- Internal Medicine Department, Bakirkoy Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
| | - Nurettin Suner
- Division of General Medicine, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
| | - Ali Kocatas
- Department of General Surgery, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, University of Health Sciences, Director of Hospital, Istanbul, Turkey.
| |
Collapse
|
|
16
|
Tavares LP, Melo EM, Sousa LP, Teixeira MM. Pro-resolving therapies as potential adjunct treatment for infectious diseases: Evidence from studies with annexin A1 and angiotensin-(1-7). Semin Immunol 2022; 59:101601. [PMID: 35219595 DOI: 10.1016/j.smim.2022.101601] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/06/2022] [Accepted: 02/17/2022] [Indexed: 01/15/2023]
Abstract
Infectious diseases, once believed to be an eradicable public health threat, still represent a leading cause of death worldwide. Environmental and social changes continuously favor the emergence of new pathogens and rapid dissemination around the world. The limited availability of anti-viral therapies and increased antibiotic resistance has made the therapeutic management of infectious disease a major challenge. Inflammation is a primordial defense to protect the host against invading microorganisms. However, dysfunctional inflammatory responses contribute to disease severity and mortality during infections. In recent years, a few studies have examined the relevance of resolution of inflammation in the context of infections. Inflammation resolution is an active integrated process transduced by several pro-resolving mediators, including Annexin A1 and Angiotensin-(1-7). Here, we examine some of the cellular and molecular circuits triggered by pro-resolving molecules and that may be beneficial in the context of infectious diseases.
Collapse
Affiliation(s)
- Luciana Pádua Tavares
- Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Eliza Mathias Melo
- Immunopharmacology Laboratory, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Lirlândia Pires Sousa
- Signaling in Inflammation Laboratory, Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
| | - Mauro Martins Teixeira
- Immunopharmacology Laboratory, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
| |
Collapse
|
|
17
|
Amezcua-Guerra LM, Del Valle L, González-Pacheco H, Springall R, Márquez-Velasco R, Massó F, Brianza-Padilla M, Manzur-Sandoval D, González-Flores J, García-Ávila C, Juárez-Vicuña Y, Sánchez-Muñoz F, Ballinas-Verdugo MA, Basilio-Gálvez E, Paez-Arenas A, Castillo-Salazar M, Cásares-Alvarado S, Hernández-Diazcouder A, Sánchez-Gloria JL, Tavera-Alonso C, Gopar-Nieto R, Sandoval J. The prognostic importance of the angiotensin II/angiotensin-(1-7) ratio in patients with SARS-CoV-2 infection. Ther Adv Respir Dis 2022; 16:17534666221122544. [PMID: 36082632 PMCID: PMC9465579 DOI: 10.1177/17534666221122544] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Background: Information about angiotensin II (Ang II), angiotensin-converting enzyme 2
(ACE2), and Ang-(1–7) levels in patients with COVID-19 is scarce. Objective: To characterize the Ang II–ACE2–Ang-(1–7) axis in patients with SARS-CoV-2
infection to understand its role in pathogenesis and prognosis. Methods: Patients greater than 18 years diagnosed with COVID-19, based on clinical
findings and positive RT-PCR test, who required hospitalization and
treatment were included. We compared Ang II, aldosterone, Ang-(1–7), and
Ang-(1–9) concentrations and ACE2 concentration and activity between
COVID-19 patients and historic controls. We compared baseline demographics,
laboratory results (enzyme, peptide, and inflammatory marker levels), and
outcome (patients who survived versus those who died). Results: Serum from 74 patients [age: 58 (48–67.2) years; 68% men] with moderate (20%)
or severe (80%) COVID-19 were analyzed. During 13 (10–21) days of
hospitalization, 25 patients died from COVID-19 and 49 patients survived.
Compared with controls, Ang II concentration was higher and Ang-(1–7)
concentration was lower, despite significantly higher ACE2 activity in
patients. Ang II concentration was higher and Ang-(1–7) concentration was
lower in patients who died. The Ang II/Ang-(1–7) ratio was significantly
higher in patients who died. In multivariate analysis, Ang II/Ang-(1–7)
ratio greater than 3.45 (OR = 5.87) and lymphocyte count
⩽0.65 × 103/µl (OR = 8.43) were independent predictors of
mortality from COVID-19. Conclusion: In patients with severe SARS-CoV-2 infection, imbalance in the Ang
II–ACE2–Ang-(1–7) axis may reflect deleterious effects of Ang II and may
indicate a worse outcome.
Collapse
Affiliation(s)
- Luis M Amezcua-Guerra
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Leonardo Del Valle
- Pharmacology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Rashidi Springall
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Felipe Massó
- Translational Medicine Lab UNAM-INC Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Daniel Manzur-Sandoval
- Intensive Care Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Carlos García-Ávila
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Yaneli Juárez-Vicuña
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Fausto Sánchez-Muñoz
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Edna Basilio-Gálvez
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Araceli Paez-Arenas
- Translational Medicine Lab UNAM-INC Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | | | | | - José L Sánchez-Gloria
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | | | - Rodrigo Gopar-Nieto
- Coronary Care Unit, Ignacio Chávez National Institute of Cardiology, Mexico City, Mexico
| | - Julio Sandoval
- Immunology Department, Ignacio Chávez National Institute of Cardiology, Juan Badiano # 1, Colonia Sección XVI Tlalpan, México City 14080, México
| |
Collapse
|
|
18
|
Zaidan I, Tavares LP, Sugimoto MA, Lima KM, Negreiros-Lima GL, Teixeira LC, Miranda TC, Valiate BV, Cramer A, Vago JP, Campolina-Silva GH, Souza JA, Grossi LC, Pinho V, Campagnole-Santos MJ, Santos RAS, Teixeira MM, Galvão I, Sousa LP. Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis. JCI Insight 2021; 7:147819. [PMID: 34874920 PMCID: PMC8765051 DOI: 10.1172/jci.insight.147819] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 11/24/2021] [Indexed: 11/17/2022] Open
Abstract
Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2–dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.
Collapse
Affiliation(s)
- Isabella Zaidan
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luciana P Tavares
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Michelle A Sugimoto
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Kátia M Lima
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Graziele L Negreiros-Lima
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Lívia Cr Teixeira
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Thais C Miranda
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Bruno Vs Valiate
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Allysson Cramer
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Juliana Priscila Vago
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Jéssica Am Souza
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Laís C Grossi
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vanessa Pinho
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Robson A S Santos
- Departamento de Fisiologia e Farmacologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro M Teixeira
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Izabela Galvão
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Lirlândia P Sousa
- Department of Clinical and Toxicological Analysis from the School of Pharma, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| |
Collapse
|
|
19
|
Camelo S, Latil M, Agus S, Dioh W, Veillet S, Lafont R, Dilda PJ. A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality. Emerg Microbes Infect 2021; 10:2256-2263. [PMID: 34783636 PMCID: PMC8648031 DOI: 10.1080/22221751.2021.2006579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 01/08/2023]
Abstract
Since December 2019, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has changed our lives. Elderly and those with comorbidities represent the vast majority of patients hospitalized with severe COVID-19 symptoms, including acute respiratory disease syndrome and cardiac dysfunction. Despite a huge effort of the scientific community, improved treatment modalities limiting the severity and mortality of hospitalized COVID-19 patients are still required. Here, we compare the effectiveness of virus- and patients-centred strategies to reduce COVID-19 mortality. We also discuss the therapeutic options that might further reduce death rates associated with the disease in the future. Unexpectedly, extensive review of the literature suggests that SARS-CoV-2 viral load seems to be associated neither with the severity of symptoms nor with mortality of hospitalized patients with COVID-19. This may explain why, so far, virus-centred strategies using antivirals aiming to inhibit the viral replicative machinery have failed to reduce COVID-19 mortality in patients with respiratory failure. By contrast, anti-inflammatory treatments without antiviral capacities but centred on patients, such as dexamethasone or Tocilizumab®, reduce COVID-19 mortality. Finally, since the spike protein of SARS-CoV-2 binds to angiotensin converting enzyme 2 and inhibits its function, we explore the different treatment options focussing on rebalancing the renin-angiotensin system. This new therapeutic strategy could hopefully further reduce the severity of respiratory failure and limit COVID-19 mortality in elderly patients.
Collapse
Affiliation(s)
| | | | - Sam Agus
- Biophytis Inc., Cambridge, MA, USA
| | - Waly Dioh
- Biophytis, Sorbonne Université, Paris, France
| | | | - René Lafont
- Biophytis, Sorbonne Université, Paris, France
- CNRS – Institut de Biologie Paris Seine (BIOSIPE), Sorbonne Université, Paris, France
| | | |
Collapse
|
|
20
|
Balakumar P, Jagadeesh G. The renin-angiotensin-aldosterone system: A century-old diversified system with several therapeutic avenues. Pharmacol Res 2021; 174:105929. [PMID: 34740819 DOI: 10.1016/j.phrs.2021.105929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 09/30/2021] [Indexed: 12/24/2022]
Affiliation(s)
- Pitchai Balakumar
- Department of Pharmacology, Pannai College of Pharmacy, Dindigul 624005, India.
| | - Gowraganahalli Jagadeesh
- Division of Pharmacology & Toxicology, Office of Cardiology, Hematology, Endocrinology, and Nephrology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
| |
Collapse
|
|
21
|
Xu B, Li G, Guo J, Ikezoe T, Kasirajan K, Zhao S, Dalman RL. Angiotensin-converting enzyme 2, coronavirus disease 2019, and abdominal aortic aneurysms. J Vasc Surg 2021; 74:1740-1751. [PMID: 33600934 PMCID: PMC7944865 DOI: 10.1016/j.jvs.2021.01.051] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/08/2021] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiologic agent of the current, world-wide coronavirus disease 2019 (COVID-19) pandemic. Angiotensin-converting enzyme 2 (ACE2) is the SARS-CoV-2 host entry receptor for cellular inoculation and target organ injury. We reviewed ACE2 expression and the role of ACE2-angiotensin 1-7-Mas receptor axis activity in abdominal aortic aneurysm (AAA) pathogenesis to identify potential COVID-19 influences on AAA disease pathogenesis. METHODS A comprehensive literature search was performed on PubMed, National Library of Medicine. Key words included COVID-19, SARS-CoV-2, AAA, ACE2, ACE or angiotensin II type 1 (AT1) receptor inhibitor, angiotensin 1-7, Mas receptor, age, gender, respiratory diseases, diabetes, and autoimmune diseases. Key publications on the epidemiology and pathogenesis of COVID-19 and AAAs were identified and reviewed. RESULTS All vascular structural cells, including endothelial and smooth muscle cells, fibroblasts, and pericytes express ACE2. Cigarette smoking, diabetes, chronic obstructive pulmonary disease, lupus, certain types of malignancies, and viral infection promote ACE2 expression and activity, with the magnitude of response varying by sex and age. Genetic deficiency of AT1 receptor, or pharmacologic ACE or AT1 inhibition also increases ACE2 and its catalytic product angiotensin 1-7. Genetic ablation or pharmacologic inhibition of ACE2 or Mas receptor augments, whereas ACE2 activation or angiotensin 1-7 treatment attenuates, progression of experimental AAAs. The potential influences of SARS-CoV-2 on AAA pathogenesis include augmented ACE-angiotensin II-AT1 receptor activity resulting from decreased reciprocal ACE2-angiotensin 1-7-Mas activation; increased production of proaneurysmal mediators stimulated by viral spike proteins in ACE2-negative myeloid cells or by ACE2-expressing vascular structural cells; augmented local or systemic cross-talk between viral targeted nonvascular, nonleukocytic ACE2-expressing cells via ligand recognition of their cognate leukocyte receptors; and hypoxemia and increased systemic inflammatory tone experienced during severe COVID-19 illness. CONCLUSIONS COVID-19 may theoretically influence AAA disease through multiple SARS-CoV-2-induced mechanisms. Further investigation and clinical follow-up will be necessary to determine whether and to what extent the COVID-19 pandemic will influence the prevalence, progression, and lethality of AAA disease in the coming decade.
Collapse
Affiliation(s)
- Baohui Xu
- Department of Surgery, Stanford University School of Medicine, Stanford, Calif.
| | - Gang Li
- Department of Surgery, Stanford University School of Medicine, Stanford, Calif
| | - Jia Guo
- Department of Surgery, Stanford University School of Medicine, Stanford, Calif
| | - Toru Ikezoe
- Department of Surgery, Stanford University School of Medicine, Stanford, Calif
| | | | - Sihai Zhao
- Department of Surgery, Stanford University School of Medicine, Stanford, Calif
| | - Ronald L Dalman
- Department of Surgery, Stanford University School of Medicine, Stanford, Calif
| |
Collapse
|
|
22
|
Legrand M, Bell S, Forni L, Joannidis M, Koyner JL, Liu K, Cantaluppi V. Pathophysiology of COVID-19-associated acute kidney injury. Nat Rev Nephrol 2021; 17:751-764. [PMID: 34226718 PMCID: PMC8256398 DOI: 10.1038/s41581-021-00452-0] [Citation(s) in RCA: 295] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2021] [Indexed: 02/06/2023]
Abstract
Although respiratory failure and hypoxaemia are the main manifestations of COVID-19, kidney involvement is also common. Available evidence supports a number of potential pathophysiological pathways through which acute kidney injury (AKI) can develop in the context of SARS-CoV-2 infection. Histopathological findings have highlighted both similarities and differences between AKI in patients with COVID-19 and in those with AKI in non-COVID-related sepsis. Acute tubular injury is common, although it is often mild, despite markedly reduced kidney function. Systemic haemodynamic instability very likely contributes to tubular injury. Despite descriptions of COVID-19 as a cytokine storm syndrome, levels of circulating cytokines are often lower in patients with COVID-19 than in patients with acute respiratory distress syndrome with causes other than COVID-19. Tissue inflammation and local immune cell infiltration have been repeatedly observed and might have a critical role in kidney injury, as might endothelial injury and microvascular thrombi. Findings of high viral load in patients who have died with AKI suggest a contribution of viral invasion in the kidneys, although the issue of renal tropism remains controversial. An impaired type I interferon response has also been reported in patients with severe COVID-19. In light of these observations, the potential pathophysiological mechanisms of COVID-19-associated AKI may provide insights into therapeutic strategies.
Collapse
Affiliation(s)
- Matthieu Legrand
- Department of Anesthesia and Perioperative Care, Division of Critical Care Medicine, University of California, San Francisco, CA, USA.
- Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists network, Nancy, France.
| | - Samira Bell
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK
| | - Lui Forni
- Intensive Care Unit, Royal Surrey Hospital NHS Foundation Trust, Surrey, UK
- Department of Clinical and Experimental Medicine, Faculty of Health Sciences, University of Surrey, Surrey, UK
| | - Michael Joannidis
- Division of Intensive Care and Emergency Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Jay L Koyner
- Divisions of Nephrology, Departments of Medicine, University of Chicago, Chicago, IL, USA
| | - Kathleen Liu
- Divisions of Nephrology and Critical Care Medicine, Departments of Medicine and Anesthesia, University of San Francisco, San Francisco, CA, USA
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| |
Collapse
|
|
23
|
Pucci F, Annoni F, dos Santos RAS, Taccone FS, Rooman M. Quantifying Renin-Angiotensin-System Alterations in COVID-19. Cells 2021; 10:2755. [PMID: 34685735 PMCID: PMC8535134 DOI: 10.3390/cells10102755] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/17/2022] Open
Abstract
The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, and therefore a lot of research has been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.
Collapse
Affiliation(s)
- Fabrizio Pucci
- 3BIO—Computational Biology and Bioinformatics, Université Libre de Bruxelles, 1050 Brussels, Belgium;
- (IB)—Interuniversity Institute of Bioinformatics in Brussels, 1050 Brussels, Belgium
| | - Filippo Annoni
- Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; (F.A.); (F.S.T.)
| | | | - Fabio Silvio Taccone
- Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; (F.A.); (F.S.T.)
| | - Marianne Rooman
- 3BIO—Computational Biology and Bioinformatics, Université Libre de Bruxelles, 1050 Brussels, Belgium;
- (IB)—Interuniversity Institute of Bioinformatics in Brussels, 1050 Brussels, Belgium
| |
Collapse
|
|
24
|
Lundström A, Ziegler L, Havervall S, Rudberg A, von Meijenfeldt F, Lisman T, Mackman N, Sandén P, Thålin C. Soluble angiotensin-converting enzyme 2 is transiently elevated in COVID-19 and correlates with specific inflammatory and endothelial markers. J Med Virol 2021; 93:5908-5916. [PMID: 34138483 PMCID: PMC8426677 DOI: 10.1002/jmv.27144] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 06/14/2021] [Indexed: 12/29/2022]
Abstract
The main entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 interactions with ACE2 may increase ectodomain shedding but consequences for the renin-angiotensin system and pathology in Coronavirus disease 2019 (COVID-19) remain unclear. We measured soluble ACE2 (sACE2) and sACE levels by enzyme-linked immunosorbent assay in 114 hospital-treated COVID-19 patients compared with 10 healthy controls; follow-up samples after four months were analyzed for 58 patients. Associations between sACE2 respectively sACE and risk factors for severe COVID-19, outcome, and inflammatory markers were investigated. Levels of sACE2 were higher in COVID-19 patients than in healthy controls, median 5.0 (interquartile range 2.8-11.8) ng/ml versus 1.4 (1.1-1.6) ng/ml, p < .0001. sACE2 was higher in men than women but was not affected by other risk factors for severe COVID-19. sACE2 decreased to 2.3 (1.6-3.9) ng/ml at follow-up, p < .0001, but remained higher than in healthy controls, p = .012. sACE was marginally lower during COVID-19 compared with at follow-up, 57 (45-70) ng/ml versus 72 (52-87) ng/ml, p = .008. Levels of sACE2 and sACE did not differ depending on survival or disease severity. sACE2 during COVID-19 correlated with von Willebrand factor, factor VIII and D-dimer, while sACE correlated with interleukin 6, tumor necrosis factor α, and plasminogen activator inhibitor 1. Conclusions: sACE2 was transiently elevated in COVID-19, likely due to increased shedding from infected cells. sACE2 and sACE during COVID-19 differed in correlations with markers of inflammation and endothelial dysfunction, suggesting release from different cell types and/or vascular beds.
Collapse
Affiliation(s)
- Annika Lundström
- Division of Neurology, Department of Clinical SciencesKarolinska Institutet Danderyd HospitalStockholmSweden
| | - Louise Ziegler
- Division of Internal Medicine, Department of Clinical SciencesKarolinska Institutet Danderyd HospitalStockholmSweden
| | - Sebastian Havervall
- Division of Internal Medicine, Department of Clinical SciencesKarolinska Institutet Danderyd HospitalStockholmSweden
| | - Ann‐Sofie Rudberg
- Division of Neurology, Department of Clinical SciencesKarolinska Institutet Danderyd HospitalStockholmSweden
| | - Fien von Meijenfeldt
- Surgical Research Laboratory, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Ton Lisman
- Surgical Research Laboratory, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Nigel Mackman
- Division of Hematology, Department of Medicine, UNC Blood Research CenterUniversity of North Carolina at Chapel HillChapel HillNorth CarolinaUSA
| | - Per Sandén
- Division of Neurology, Department of Clinical SciencesKarolinska Institutet Danderyd HospitalStockholmSweden
| | - Charlotte Thålin
- Division of Internal Medicine, Department of Clinical SciencesKarolinska Institutet Danderyd HospitalStockholmSweden
| |
Collapse
|
|
25
|
Henry BM, Benoit JL, Rose J, de Oliveira MHS, Lippi G, Benoit SW. Serum ACE activity and plasma ACE concentration in patients with SARS-CoV-2 infection. Scandinavian Journal of Clinical and Laboratory Investigation 2021; 81:272-275. [PMID: 34003706 PMCID: PMC8146290 DOI: 10.1080/00365513.2021.1926536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Significant controversy has arisen over the role of the renin-angiotensin-aldosterone system (RAAS) in COVID-19 pathophysiology. In this prospective, observational study, we evaluated plasma angiotensin converting enzyme (ACE) concentration and serum ACE activity in 52 adults with laboratory-confirmed SARS-CoV-2 infection and 27 non-COVID-19 sick controls. No significant differences were observed in ACE activity in COVID-19 patients versus non-COVID-19 sick controls (41.1 [interquartile range (IQR): 23.0–55.2] vs. 42.9 [IQR 13.6–74.2] U/L, p = .649, respectively). Similarly, no differences were observed in ACE concentration in COVID-19 patients versus non-COVID-19 sick controls (108.4 [IQR: 95.8–142.2] vs. 133.8 [IQR: 100.2–173.7] μg/L, p = .059, respectively). Neither ACE activity (p = .751), nor ACE concentration (p = .283) was associated with COVID-19 severity. Moreover, neither ACE activity, nor ACE concentration was correlated with any inflammatory biomarkers.
Collapse
Affiliation(s)
- Brandon Michael Henry
- The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Justin L Benoit
- Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - James Rose
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, OH, USA
| | | | - Giuseppe Lippi
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
| | - Stefanie W Benoit
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, OH, USA.,Department of Pediatrics, University of Cincinnati, College of Medicine, OH, USA
| |
Collapse
|
|
26
|
Rysz S, Al-Saadi J, Sjöström A, Farm M, Campoccia Jalde F, Plattén M, Eriksson H, Klein M, Vargas-Paris R, Nyrén S, Abdula G, Ouellette R, Granberg T, Jonsson Fagerlund M, Lundberg J. COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system. Nat Commun 2021; 12:2417. [PMID: 33893295 PMCID: PMC8065208 DOI: 10.1038/s41467-021-22713-z] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance.
Collapse
Affiliation(s)
- Susanne Rysz
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
| | - Jonathan Al-Saadi
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Anna Sjöström
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden
| | - Maria Farm
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden
| | - Francesca Campoccia Jalde
- Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Michael Plattén
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Helen Eriksson
- Department of Sociology, Stockholm University Demography Unit, Stockholm University, Stockholm, Sweden
| | - Margareta Klein
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Radiology Huddinge, Karolinska University Hospital, Stockholm, Sweden
| | - Roberto Vargas-Paris
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Radiology Solna, Karolinska University Hospital, Stockholm, Sweden
| | - Sven Nyrén
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Radiology Solna, Karolinska University Hospital, Stockholm, Sweden
| | - Goran Abdula
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden
| | - Russell Ouellette
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Tobias Granberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
| | - Malin Jonsson Fagerlund
- Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Johan Lundberg
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
- Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
| |
Collapse
|
|
27
|
Oz M, Lorke DE. Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury. Biomed Pharmacother 2021; 136:111193. [PMID: 33461019 PMCID: PMC7836742 DOI: 10.1016/j.biopha.2020.111193] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/15/2020] [Accepted: 12/26/2020] [Indexed: 12/11/2022] Open
Abstract
The recent emergence of coronavirus disease-2019 (COVID-19) as a pandemic affecting millions of individuals has raised great concern throughout the world, and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was identified as the causative agent for COVID-19. The multifunctional protein angiotensin converting enzyme 2 (ACE2) is accepted as its primary target for entry into host cells. In its enzymatic function, ACE2, like its homologue ACE, regulates the renin-angiotensin system (RAS) critical for cardiovascular and renal homeostasis in mammals. Unlike ACE, however, ACE2 drives an alternative RAS pathway by degrading Ang-II and thus operates to balance RAS homeostasis in the context of hypertension, heart failure, and cardiovascular as well as renal complications of diabetes. Outside the RAS, ACE2 hydrolyzes key peptides, such as amyloid-β, apelin, and [des-Arg9]-bradykinin. In addition to its enzymatic functions, ACE2 is found to regulate intestinal amino acid homeostasis and the gut microbiome. Although the non-enzymatic function of ACE2 as the entry receptor for SARS-CoV-2 has been well established, the contribution of enzymatic functions of ACE2 to the pathogenesis of COVID-19-related lung injury has been a matter of debate. A complete understanding of this central enzyme may begin to explain the various symptoms and pathologies seen in SARS-CoV-2 infected individuals, and may aid in the development of novel treatments for COVID-19.
Collapse
Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait.
| | - Dietrich Ernst Lorke
- Department of Anatomy and Cellular Biology, Khalifa University, Abu Dhabi, United Arab Emirates; Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| |
Collapse
|
|
28
|
Latil M, Camelo S, Veillet S, Lafont R, Dilda PJ. Developing new drugs that activate the protective arm of the renin-angiotensin system as a potential treatment for respiratory failure in COVID-19 patients. Drug Discov Today 2021; 26:1311-1318. [PMID: 33609783 PMCID: PMC7888990 DOI: 10.1016/j.drudis.2021.02.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 12/02/2020] [Accepted: 02/08/2021] [Indexed: 12/18/2022]
Abstract
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has reached pandemic proportions with negative impacts on global health, the world economy and human society. The clinical picture of COVID-19, and the fact that Angiotensin converting enzyme 2 (ACE2) is a receptor of SARS-CoV-2, suggests that SARS-CoV-2 infection induces an imbalance in the renin–angiotensin system (RAS). We review clinical strategies that are attempting to rebalance the RAS in COVID-19 patients by using ACE inhibitors, angiotensin receptor blockers, or agonists of angiotensin-II receptor type 2 or Mas receptor (MasR). We also propose that the new MasR activator BIO101, a pharmaceutical grade formulation of 20-hydroxyecdysone that has anti-inflammatory, anti-fibrotic and cardioprotective properties, could restore RAS balance and improve the health of COVID-19 patients who have severe pneumonia.
Collapse
Affiliation(s)
- Mathilde Latil
- Biophytis, Sorbonne Université - BC9, 4 Place Jussieu, 75005 Paris, France
| | - Serge Camelo
- Biophytis, Sorbonne Université - BC9, 4 Place Jussieu, 75005 Paris, France
| | - Stanislas Veillet
- Biophytis, Sorbonne Université - BC9, 4 Place Jussieu, 75005 Paris, France
| | - René Lafont
- Biophytis, Sorbonne Université - BC9, 4 Place Jussieu, 75005 Paris, France; Sorbonne Université, CNRS - Institut de Biologie Paris Seine (BIOSIPE), 75005 Paris, France
| | - Pierre J Dilda
- Biophytis, Sorbonne Université - BC9, 4 Place Jussieu, 75005 Paris, France.
| |
Collapse
|