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1
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Li X, Qu S. Novel insights into the central protective role of ACE2 in diabetic cardiomyopathy: from underlying signaling pathways to therapeutic perspectives. Mol Cell Biochem 2025; 480:3535-3551. [PMID: 39928210 DOI: 10.1007/s11010-024-05196-6] [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: 11/02/2024] [Accepted: 12/18/2024] [Indexed: 02/11/2025]
Abstract
Diabetic cardiomyopathy (DCM) is a cardiac complication specific to individuals with diabetes. It is defined as abnormalities of myocardial structure and function in diabetic patients who do not exhibit any obvious coronary artery disease, hypertensive heart disease, valvular heart disease, or inherited cardiomyopathy. A significant cardiovascular protective factor identified recently is angiotensin-converting enzyme 2 (ACE2), which is a rising star in the renin angiotensin system (RAS) and is responsible for the onset and progression of DCM. Nonetheless, there is not a comprehensive review outlining ACE2's effect on DCM. From the perspective of the pathogenesis of DCM, this review summarizes the myocardial protective role of ACE2 in the aspects of alleviating myocardial structure and dysfunction, correcting energy metabolism disorders, and restoring vascular function. Concurrently, we propose the connections between ACE2 and underlying signaling pathways, including ADAM17, Apelin/APJ, and Nrf2. Additionally, we highlight ACE2-related pharmaceutical treatment options and clinical application prospects for preventing and managing DCM. Further and underlying research is extensively required to completely comprehend the principal pathophysiological mechanism of DCM and the distinctive function of ACE2, switching experimental findings into clinical practice and identifying efficient therapeutic approaches.
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Affiliation(s)
- Xinyi Li
- Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shunlin Qu
- Pathophysiology Department, Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, University of South China, Hongxiang Street, Hengyang, 421001, Hunan, China.
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2
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Roman-Pepine D, Serban AM, Capras RD, Cismaru CM, Filip AG. A Comprehensive Review: Unraveling the Role of Inflammation in the Etiology of Heart Failure. Heart Fail Rev 2025:10.1007/s10741-025-10519-w. [PMID: 40360833 DOI: 10.1007/s10741-025-10519-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/27/2025] [Indexed: 05/15/2025]
Abstract
Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. This comprehensive review aims to elucidate the intricate mechanisms by which inflammation contributes to the development and progression of HF. The review synthesizes current research on the involvement of both innate and adaptive immune responses in HF, highlighting the roles of cytokines, chemokines, and other inflammatory mediators. Recent studies have demonstrated that chronic inflammation, driven by factors such as oxidative stress, neurohormonal activation, and metabolic disturbances, leads to adverse cardiac remodeling and impaired myocardial function. The review explores how systemic inflammation, characterized by elevated levels of inflammatory biomarkers like C-reactive protein (CRP) and interleukin-6 (IL-6), correlates with HF severity and outcomes. Additionally, it discusses the impact of comorbid conditions such as diabetes, obesity, and hypertension on inflammatory pathways and HF risk. The review also delves into the therapeutic implications of targeting inflammation in HF. Despite mixed results from early clinical trials, emerging evidence suggests that anti-inflammatory therapies offer benefits in specific HF phenotypes. The potential of novel therapeutic strategies, including the use of biologics and small molecule inhibitors, is examined in the context of their ability to modulate inflammatory responses and improve clinical outcomes.
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Affiliation(s)
- Diana Roman-Pepine
- Department of Anatomy and Embryology, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania.
- Cardiology Department, Heart Institute Niculae Stăncioiu, 19-21 Motilor Street, 400001, Cluj-Napoca- Napoca, Romania.
| | - Adela Mihaela Serban
- Cardiology Department, Heart Institute Niculae Stăncioiu, 19-21 Motilor Street, 400001, Cluj-Napoca- Napoca, Romania
- 5 Th Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
| | - Roxana-Denisa Capras
- Department of Anatomy and Embryology, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
| | - Cristina Mihaela Cismaru
- Department of Infectious Diseases, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
| | - Adriana Gabriela Filip
- Department of Anatomy and Embryology, Iuliu Hatieganu University of Medicine and Pharmacy, 400348, Cluj-Napoca-Napoca, Romania
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3
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Vanderkamp SG, Niazy M, Stegelmeier AA, Stinson KJ, Ricker N, Bridle BW. Cytokine, chemokine, and acute-phase protein profiles in plasma as correlative biomarkers of clinical outcomes for patients with COVID-19. Sci Rep 2025; 15:15397. [PMID: 40316702 PMCID: PMC12048561 DOI: 10.1038/s41598-025-99248-6] [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: 06/28/2024] [Accepted: 04/17/2025] [Indexed: 05/04/2025] Open
Abstract
Coronavirus disease identified in 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2, had a global impact on human health and the economy. The aim of this study was to quantify cytokines, chemokines, and acute phase proteins in the plasma of patients with COVID-19 to elucidate potential biomarkers to inform prognostic and treatment decisions. Clustering analysis using the K-prototypes method identified underlying biological patterns in patients with COVID-19. The penalized multinomial logistic regression analysis identified two comorbidities (hypertension, congestive heart failure) and thirteen analytes as potential risk factors for COVID-19 progression with 88.2% accuracy. Based on a patient's age, high concentrations of interleukin (IL)-6, monocyte chemoattractant protein-1, and pentraxin 3 were important biomarkers for lethal COVID-19. Decreased concentrations of interferon gamma-induced protein-10, IL-10, and soluble tumor necrosis factor receptor I were found to be associated with mild COVID-19, while increasing concentrations of these analytes could be used to predict COVID-19 severity.
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Affiliation(s)
- Sierra G Vanderkamp
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Maysa Niazy
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Ashley A Stegelmeier
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | | | - Nicole Ricker
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada.
| | - Byram W Bridle
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, N1G 2W1, Canada.
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4
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Amiral J, Ferol R. Update on the measurement of "soluble angiotensin converting enzyme 2" in plasma and its emerging significance as a novel biomarker of cardiovascular and kidney diseases: A concise commentary. Transfus Apher Sci 2025; 64:104090. [PMID: 39923730 DOI: 10.1016/j.transci.2025.104090] [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] [Indexed: 02/11/2025]
Abstract
Angiotensin Converting Enzyme 2 has emerged as a major cell-surface enzyme receptor for controlling the Renin-Angiotensin-Aldosterone-System. The SARS-Cov-2 pandemics has focused a major interest on that cell-surface receptor. It is the virus entry door for cell infection, and when inside it can replicate and lead to cell destruction. In some physio-pathological conditions, ADAM 17 and TMPSSR2 enzymes can cleave ACE2 on the cell surface and release its extra-cellular domain into the blood circulation. Measurement of this soluble protein then becomes possible, preferentially in plasma, but also in serum. Clinical studies have shown that Soluble ACE2 is an emerging biomarker for cardiovascular and kidney diseases and it could be of prognostic value for heart failure and kidney dysfunctions. In Covid-19 its diagnostic value is controversial, and the various studies lead to different conclusions. Many laboratory assays have been reported for the measurement of this biomarker. They concern enzymatic assays, aptamer methods, or immunoassays, either chemiluminescent or ELISA. Normal and pathological plasma concentrations reported with the various assays yet lack standardization and are very heterogenous. Recently introduced immunoassays tend to yield more compliant results despite variations due to the assay design and calibration, or the antibody targeted epitopes and reactivity. This article reports an ELISA designed with affinity purified rabbit polyclonal antibodies, obtained with recombinant ACE2 and calibrated with the recombinant protein in plasma. This assay has a global reactivity with the various ACE2 protein epitopes. Assay performance characteristics, and values measured in normal populations are presented. Availability of optimized ELISAs can contribute to a better harmonization of sACE2 measurements in plasma, and confirm its clinical significance as biomarker.
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Affiliation(s)
- Jean Amiral
- Scientific Hemostasis, Franconville, France.
| | - Rémy Ferol
- Scientific Hemostasis, Franconville, France
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5
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Yang J, Ma C, Feng Z, Xiao F, Kang Y, Zhang W, Liao X. Soluble CD72 concurrently impairs T cell functions while enhances inflammatory response in sepsis. Int Immunopharmacol 2025; 147:113981. [PMID: 39793226 DOI: 10.1016/j.intimp.2024.113981] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/24/2024] [Accepted: 12/28/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Sepsis is defined as multi-organ dysfunction caused by dysregulated host response to infection. This dysregulated host response includes enhanced inflammatory responses and suppressed adaptive immunity, but the molecular mechanisms behind it have not yet been elucidated. CD72, a type II transmembrane protein that is primarily expressed in B cells, was found to play an immunomodulatory role in the immune system and was associated with mortality in patients with sepsis. However, whether CD72 affects the pathogenesis of sepsis by influencing the immune response remains unclear. METHODS We first collected peripheral blood from 40 healthy volunteers and 57 septic patients and analyzed the mRNA levels of CD72 and the expression of its soluble form sCD72 using Realtime-PCR and ELISA. We then employed the CRISPR/Cas9 system to generate CD72 knockout mice (CD72-KO) and established a cecal ligation and puncture (CLP) model to analyze the effects of CD72 gene deletion on the survival, organ injury and immune response of septic mice by Kaplan-Meier survival analysis, pathological sections and flow cytometry. We also observe the effects of excess sCD72 on survival and immune response in sepsis by injecting recombinant CD72 protein into mice. Finally, the mechanism of sCD72 affecting sepsis immunity was analyzed by fluorescence staining, confocal microscopy and flow cytometry. RESULTS We found that when sepsis occurs, the levels of CD72 mRNA and cell surface CD72 in immune cells decrease, while the level of soluble sCD72 in the blood increases significantly. Excessive sCD72 increased sepsis mortality in a dose-dependent manner, which can bind to CD100 on the surface of T cells and enter the cytoplasm, leading to impaired T cell functions, including a decrease in CD4+IFN-γ+, CD8+Perforin+, CD8+GZMB+, and CD8+FASL+ population and an increase in inflammatory CD4+TNF-α+ population, thereby suppressing adaptive immunity while enhancing inflammatory response. CONCLUSION The immunosuppression of sepsis has been recognized, but the underlying mechanism has not been fully elucidated. Our study identified for the first time that sCD72 is an important mediator that cause adaptive immunosuppression during sepsis, which leads to T cell suppression by competitively binding to CD100 on the surface of T cells. Our study provides novel insights in our understanding of sepsis-related immunosuppression and may provide translational opportunities for the design of new diagnostic biomarkers and therapeutic targets for sepsis.
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MESH Headings
- Animals
- Sepsis/immunology
- Humans
- Antigens, Differentiation, B-Lymphocyte/genetics
- Antigens, Differentiation, B-Lymphocyte/metabolism
- Antigens, Differentiation, B-Lymphocyte/immunology
- Antigens, Differentiation, B-Lymphocyte/blood
- Mice, Knockout
- Male
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Antigens, CD/immunology
- Mice
- Female
- Mice, Inbred C57BL
- Inflammation/immunology
- T-Lymphocytes/immunology
- Disease Models, Animal
- Middle Aged
- Adult
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Affiliation(s)
- Jing Yang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, China
| | - Chengyong Ma
- Department of Critical Care Medicine, West China Hospital, Sichuan University, China
| | - Zhongxue Feng
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, China
| | - Fei Xiao
- Department of Intensive Care Unit of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, China
| | - Yan Kang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, China.
| | - Wei Zhang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, China.
| | - Xuelian Liao
- Department of Critical Care Medicine, West China Hospital, Sichuan University, China.
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6
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Takeshita H, Yamamoto K, Mogi M, Rakugi H. Muscle mass, muscle strength and the renin-angiotensin system. Clin Sci (Lond) 2024; 138:1561-1577. [PMID: 39718491 DOI: 10.1042/cs20220501] [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: 01/26/2023] [Revised: 11/19/2024] [Accepted: 11/25/2024] [Indexed: 12/25/2024]
Abstract
The renin-angiotensin system (RAS) is a classically known circulatory regulatory system. In addition to the previously known multi-organ circulatory form of the RAS, the existence of tissue RASs in individual organs has been well established. Skeletal muscle has also been identified as an organ with a distinct RAS. In recent years, the effects of RAS activation on skeletal muscle have been elucidated from several perspectives: differences in motor function due to genetic polymorphisms of RAS components, skeletal muscle dysfunction under conditions of excessive RAS activation such as heart failure, and the effects of the use of RAS inhibitors on muscle strength. In addition, the concept of the RAS itself has recently been expanded with the discovery of a 'protective arm' of the RAS formed by factors such as angiotensin-converting enzyme 2 and angiotensin 1-7. This has led to a new understanding of the physiological function of the RAS in skeletal muscle. This review summarizes the diverse physiological functions of the RAS in skeletal muscle and considers the potential of future therapeutic strategies targeting the RAS to overcome problems such as sarcopenia and muscle weakness associated with chronic disease.
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Affiliation(s)
- Hikari Takeshita
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Medical Science Technology, Faculty of Medical Science Technology, Morinomiya University of Medical Sciences, Osaka, Osaka, Japan
| | - Koichi Yamamoto
- Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Masaki Mogi
- Department of Pharmacology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
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7
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Mendiola-Salazar XA, Munguía-Laguna MA, Franco M, Cano-Martínez A, Santamaría Sosa J, Bautista-Pérez R. SARS-CoV-2 Spike Protein Enhances Carboxypeptidase Activity of Angiotensin-Converting Enzyme 2. Int J Mol Sci 2024; 25:6276. [PMID: 38892464 PMCID: PMC11172802 DOI: 10.3390/ijms25116276] [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: 04/28/2024] [Revised: 05/30/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
In this study, we investigated whether severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein may modify angiotensin-converting enzyme 2 (ACE2) activity in the plasma, heart, kidney, liver, lung, and six brain regions (amygdala, brain stem, cortex, hippocampus, hypothalamus, and striatum) of diabetic and hypertensive rats. We determine ACE2 activity in the plasma and lysates of heart, kidney, liver, lung, and six brain regions. MLN-4760 inhibits ACE2 activity in the plasma and all organs. On the other hand, soluble ACE2 (sACE2) activity increased in the plasma of diabetic rats, and there was no change in the plasma of hypertensive rats. ACE2 activity was augmented in the liver, brain stem, and striatum, while it decreased in the kidney, amygdala, cortex, and hippocampus of diabetic rats. ACE2 activity increased in the kidney, liver, and lung, while it decreased in the heart, amygdala, cortex, and hypothalamus of hypertensive rats. We measured the ACE2 content via enzyme-linked immunosorbent assay and found that ACE2 protein levels increased in the heart, while it decreased in the plasma, kidney, brain stem, cortex, hippocampus, hypothalamus, and striatum of diabetic rats. ACE2 protein levels decreased in the brain stem, cortex, hippocampus, and hypothalamus of hypertensive rats. Our data showed that the spike protein enhanced ACE2 activity in the liver and lungs of diabetic rats, as well as in the heart and three of the brain regions (cortex, hypothalamus, and striatum) of hypertensive rats.
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Affiliation(s)
- Xóchitl Andrea Mendiola-Salazar
- Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico (M.A.M.-L.)
- Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico City 54090, Mexico
| | - Melanie A. Munguía-Laguna
- Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico (M.A.M.-L.)
| | - Martha Franco
- Department of Cardio-Renal Pathophysiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico; (M.F.); (J.S.S.)
| | - Agustina Cano-Martínez
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico;
| | - José Santamaría Sosa
- Department of Cardio-Renal Pathophysiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico; (M.F.); (J.S.S.)
| | - Rocío Bautista-Pérez
- Department of Molecular Biology, Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico (M.A.M.-L.)
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8
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Boulet J, Sridhar VS, Bouabdallaoui N, Tardif JC, White M. Inflammation in heart failure: pathophysiology and therapeutic strategies. Inflamm Res 2024; 73:709-723. [PMID: 38546848 PMCID: PMC11058911 DOI: 10.1007/s00011-023-01845-6] [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: 09/07/2023] [Revised: 11/09/2023] [Accepted: 12/19/2023] [Indexed: 04/30/2024] Open
Abstract
A role for inflammation in the development and progression of heart failure (HF) has been proposed for decades. Multiple studies have demonstrated the potential involvement of several groups of cytokines and chemokines in acute and chronic HF, though targeting these pathways in early therapeutic trials have produced mixed results. These studies served to highlight the complexity and nuances of how pro-inflammatory pathways contribute to the pathogenesis of HF. More recent investigations have highlighted how inflammation may play distinct roles based on HF syndrome phenotypes, findings that may guide the development of novel therapies. In this review, we propose a contemporary update on the role of inflammation mediated by the innate and adaptive immune systems with HF, highlighting differences that exist across the ejection fraction spectrum. This will specifically be looked at through the lens of established and novel biomarkers of inflammation. Subsequently, we review how improvements in inflammatory pathways may mediate clinical benefits of existing guideline-directed medical therapies for HF, as well as future therapies in the pipeline targeting HF and inflammation.
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Affiliation(s)
- Jacinthe Boulet
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON, Canada
| | - Nadia Bouabdallaoui
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada
| | - Jean-Claude Tardif
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada
| | - Michel White
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, QC, H1C 1C8, Montreal, Canada.
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9
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Kellum CL, Kirkland LG, Nelson TK, Jewett SM, Rytkin E, Efimov IR, Hoover DB, Benson PV, Wagener BM. Sympathetic remodeling and altered angiotensin-converting enzyme 2 localization occur in patients with cardiac disease but are not exacerbated by severe COVID-19. Auton Neurosci 2024; 251:103134. [PMID: 38101169 PMCID: PMC10872860 DOI: 10.1016/j.autneu.2023.103134] [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: 08/30/2023] [Revised: 11/08/2023] [Accepted: 11/25/2023] [Indexed: 12/17/2023]
Abstract
PURPOSE Remodeling of sympathetic nerves and ACE2 has been implicated in cardiac pathology, and ACE2 also serves as a receptor for SARS-CoV-2. However, there is limited histological knowledge about the transmural distribution of sympathetic nerves and the cellular localization and distribution of ACE2 in human left ventricles from normal or diseased hearts. Goals of this study were to establish the normal pattern for these parameters and determine changes that occurred in decedents with cardiovascular disease alone compared to those with cardiac pathology and severe COVID-19. METHODS We performed immunohistochemical analysis on sections of left ventricular wall from twenty autopsied human hearts consisting of a control group, a cardiovascular disease group, and COVID-19 ARDS, and COVID-19 non-ARDS groups. RESULTS Using tyrosine hydroxylase as a noradrenergic marker, we found substantial sympathetic nerve loss in cardiovascular disease samples compared to controls. Additionally, we found heterogeneous nerve loss in both COVID-19 groups. Using an ACE2 antibody, we observed robust transmural staining localized to pericytes in the control group. The cardiovascular disease hearts displayed regional loss of ACE2 in pericytes and regional increases in staining of cardiomyocytes for ACE2. Similar changes were observed in both COVID-19 groups. CONCLUSIONS Heterogeneity of sympathetic innervation, which occurs in cardiac disease and is not increased by severe COVID-19, could contribute to arrhythmogenesis. The dominant localization of ACE2 to pericytes suggests that these cells would be the primary target for potential cardiac infection by SARS-CoV-2. Regional changes in ACE2 staining by myocytes and pericytes could have complex effects on cardiac pathophysiology.
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Affiliation(s)
- Creighton L Kellum
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Logan G Kirkland
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Tasha K Nelson
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Seth M Jewett
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Eric Rytkin
- Department of Biomedical Engineering and Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Igor R Efimov
- Department of Biomedical Engineering and Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Donald B Hoover
- Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN 37614, USA
| | - Paul V Benson
- Department of Pathology, The University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL 35294, USA
| | - Brant M Wagener
- Department of Anesthesiology and Perioperative Medicine, The University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, AL 35294, USA.
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10
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Siratavičiūtė V, Pangonytė D, Utkienė L, Jusienė L, Marcinkevičienė J, Stanionienė Z, Radikė R. Myocardial Angiotensin-Converting Enzyme 2 Protein Expression in Ischemic Heart Failure. Int J Mol Sci 2023; 24:17145. [PMID: 38138974 PMCID: PMC10743033 DOI: 10.3390/ijms242417145] [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: 11/06/2023] [Revised: 11/27/2023] [Accepted: 12/02/2023] [Indexed: 12/24/2023] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2)-angiotensin-(1-7)-Mas receptor axis plays a significant role in regulating myocardial remodeling and the development of heart failure (HF), with ACE2 being the primary focus. However, contemporary understanding of the membrane-bound form of the human ACE2 protein remains insufficient. The purpose of this study was to determine the expression of ACE2 protein in different cells of the left ventricular myocardium in non-diseased hearts and at various stages of ischemic HF. A total of 103 myocardial tissue samples from the left ventricle underwent quantitative and semi-quantitative immunohistochemical analysis. Upon assessing ACE2 immunostaining in all myocardial cells through unselective digital image analysis, there was no change in the stage A HF group. Nevertheless, the expression of ACE2 membrane protein in cardiomyocytes showed a tendency to increase, while non-cardiomyocyte ACE2 expression decreased significantly (p < 0.001). In the stage B HF group, the intensity of ACE2 immunostaining continued to increase with rising cardiomyocyte ACE2 expression (p < 0.001). Non-cardiomyocyte expression, in contrast, remained similar to that observed in the stage A HF group. In the stages C/D HF group, ACE2 expression reached its highest level in cardiomyocytes (p < 0.001), while ACE2 expression in non-cardiomyocytes was the lowest (p < 0.001). These changes in ACE2 protein levels are associated with left ventricular remodeling in ischemic HF.
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Affiliation(s)
| | - Dalia Pangonytė
- Laboratory of Cardiac Pathology, Institute of Cardiology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania; (V.S.); (L.U.); (L.J.); (J.M.); (Z.S.); (R.R.)
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11
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Benedetti S, Sisti D, Vandini D, Barocci S, Sudano M, Carlotti E, Teng JLL, Zamai L. Circulating ACE2 level and zinc/albumin ratio as potential biomarkers for a precision medicine approach to COVID-19. Adv Biol Regul 2023; 89:100973. [PMID: 37257289 PMCID: PMC10202900 DOI: 10.1016/j.jbior.2023.100973] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 05/15/2023] [Accepted: 05/22/2023] [Indexed: 06/02/2023]
Abstract
Highly mutable influenza is successfully countered based on individual susceptibility and similar precision-like medicine approach should be effective against SARS-COV-2. Among predictive markers to bring precision medicine to COVID-19, circulating ACE2 has potential features being upregulated in both severe COVID-19 and predisposing comorbidities. Spike SARS-CoVs were shown to induce ADAM17-mediated shedding of enzymatic active ACE2, thus accounting for its increased activity that has also been suggested to induce positive feedback loops leading to COVID-19-like manifestations. For this reason, pre-existing ACE2 activity and inhibition of ACE2/ADAM17 zinc-metalloproteases through zinc chelating agents have been proposed to predict COVID-19 outcome before infection and to protect from COVID-19, respectively. Since most diagnostic laboratories are not equipped for enzymatic activity determination, other potential predictive markers of disease progression exploitable by diagnostic laboratories were explored. Concentrations of circulating albumin, zinc, ACE2 protein and its activity were investigated in healthy, diabetic (COVID-19-susceptible) and SARS-CoV-2-negative COVID-19 individuals. ACE2 both protein levels and activity significantly increased in COVID-19 and diabetic patients. Abnormal high levels of ACE2 characterised a subgroup (16-19%) of diabetics, while COVID-19 patients were characterised by significantly higher zinc/albumin ratios, pointing to a relative increase of albumin-unbound zinc species, such as free zinc ones. Data on circulating ACE2 levels are in line with the hypothesis that they can drive susceptibility to COVID-19 and elevated zinc/albumin ratios support the therapeutic use of zinc chelating inhibitors of ACE2/ADAM17 zinc-metalloproteases in a targeted therapy for COVID-19.
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Affiliation(s)
- Serena Benedetti
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029, Urbino, Italy
| | - Davide Sisti
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029, Urbino, Italy
| | - Daniela Vandini
- Department of Clinical Pathology, ASUR Marche AV1, Urbino, PU, Italy
| | - Simone Barocci
- Department of Clinical Pathology, ASUR Marche AV1, Urbino, PU, Italy
| | - Maurizio Sudano
- Diabetology and Endocrinology Unit, ASUR Marche AV1, Urbino, PU, Italy
| | | | - Jade Lee Lee Teng
- Faculty of Dentistry, The University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Loris Zamai
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029, Urbino, Italy; INFN-Gran Sasso National Laboratory, Assergi, 67100, L'Aquila, Italy.
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12
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Zhou G, Liu J. Prognostic value of elevated plasma angiotensin-converting enzyme 2 in cardiometabolic diseases: A review. Medicine (Baltimore) 2023; 102:e33251. [PMID: 36897667 PMCID: PMC9997766 DOI: 10.1097/md.0000000000033251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/22/2023] [Indexed: 03/11/2023] Open
Abstract
Angiotensin-converting enzyme 2, as an internal anti regulator of the renin-angiotensin hormone cascade reaction, plays a protective role in vasodilation, inhibition of fibrosis, and initiation of anti-inflammatory and antioxidative stress by degrading angiotensin II and generating angiotensin (1-7). Multiple studies have shown that plasma angiotensin-converting enzyme 2 activity is low in healthy populations without significant cardiometabolic disease, and elevated plasma angiotensin-converting enzyme 2 levels can be used as a novel biomarker of abnormal myocardial structure and/or adverse events in cardiometabolic diseases. This article aims to elaborate the determinants of plasma angiotensin-converting enzyme 2 concentration, the relevance between angiotensin-converting enzyme 2 and cardiometabolic disease risk markers, and its relative importance compared with known cardiovascular disease risk factors. Confronted with the known cardiovascular risk factors, plasma angiotensin-converting enzyme 2 (ACE2) concentration uniformly emerged as a firm predictor of abnormal myocardial structure and/or adverse events in cardiometabolic diseases and may improve the risk prediction of cardiometabolic diseases when combined with other conventional risk factors. Cardiovascular disease is the leading cause of death worldwide, while the renin-angiotensin system is the main hormone cascade system involved in the pathophysiology of cardiovascular disease. A multi-ancestry global cohort study from the general population by Narula et al revealed that plasma ACE2 concentration was strongly associated with cardiometabolic disease and might be an easily measurable indicator of renin-angiotensin system disorder. The association between this atypical hormone disorder marker and cardiometabolic disease is isolated from conventional cardiac risk factors and brain natriuretic peptide, suggesting that a clearer comprehending of the changes in plasma ACE2 concentration and activity may help us to improve the risk prediction of cardiometabolic disease, guide early diagnosis and feasible therapies, and develop and test new therapeutic targets.
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Affiliation(s)
- Gang Zhou
- Department of First Clinical Medical College, Guangxi Medical University, Nanning, Guangxi, China
| | - Jingchen Liu
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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13
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Chen H, Peng J, Wang T, Wen J, Chen S, Huang Y, Zhang Y. Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic. Biochem Pharmacol 2023; 208:115370. [PMID: 36481346 PMCID: PMC9721294 DOI: 10.1016/j.bcp.2022.115370] [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: 10/12/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular disease is the major cause of mortality and disability, with hypertension being the most prevalent risk factor. Excessive activation of the renin-angiotensin system (RAS) under pathological conditions, leading to vascular remodeling and inflammation, is closely related to cardiovascular dysfunction. The counter-regulatory axis of the RAS consists of angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7), angiotensin (1-9), alamandine, proto-oncogene Mas receptor, angiotensin II type-2 receptor and Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the overactivated RAS. In this review, we summarize the latest insights into the complexity and interplay of the counter-regulatory RAS axis in hypertension, highlight the pathophysiological functions of ACE2, a multifunctional molecule linking hypertension and COVID-19, and discuss the function and therapeutic potential of targeting this counter-regulatory RAS axis to prevent and treat hypertension in the context of the current COVID-19 pandemic.
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Affiliation(s)
- Hongyin Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518000, Guangdong, China
| | - Jiangyun Peng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Tengyao Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Jielu Wen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China,Corresponding authors
| | - Yang Zhang
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518000, Guangdong, China,Corresponding authors
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14
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Zamai L. Hypothesis: Efficacy of early treatments with some NSAIDs in COVID-19: Might it also depend on their direct and/or indirect zinc chelating ability? Br J Pharmacol 2023; 180:279-286. [PMID: 36482040 PMCID: PMC9877557 DOI: 10.1111/bph.15989] [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: 09/10/2022] [Accepted: 11/10/2022] [Indexed: 12/13/2022] Open
Abstract
The present work argues for the involvement of the zinc chelating ability of some non-steroidal anti-inflammatory drugs as an additive mechanism able to increase their efficacy against COVID-19.
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Affiliation(s)
- Loris Zamai
- Department of Biomolecular SciencesUniversity of Urbino Carlo BoUrbinoItaly,National Institute for Nuclear Physics (INFN)—Gran Sasso National Laboratory (LNGS)L'AquilaItaly
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15
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Kamthe DD, Sarangkar SD, Dalvi MS, Gosavi NA, Nikam VS. Angiotensin converting enzyme 2 level and its significance in COVID-19 and other diseases patients. Eur J Clin Invest 2023; 53:e13891. [PMID: 36222740 PMCID: PMC9874405 DOI: 10.1111/eci.13891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 10/03/2022] [Accepted: 10/11/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Angiotensin-converting enzyme 2 (ACE2) expressions and its modulation are of great interest as being a key receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and the protective arm of the rennin-angiotensin axis, maintaining cardiovascular homeostasis. However, ACE2 expressions and their modulation in the healthy and disease background are yet to be explored. METHOD We performed a meta-analysis, extracting the data for ACE2 expression in human subjects with various diseases, including SARS-CoV2 infection without or with co-morbidity. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Out of 203 studies, 39 met the inclusion criteria with SARS-CoV2 patients without co-morbidity, SARS-CoV2 patients with co-morbidity, cardiovascular (CVD) patients, diabetes patients, kidney disorders patients, pulmonary disease patients, and other viral infections patients. RESULTS Angiotensin-converting enzyme 2 expression was significantly increased in all diseases. There was an elevated level of ACE2, especially membrane-bound ACE2, in COVID-19 patients compared to healthy controls. A statistically significant increase in ACE2 expression was observed in CVD patients and patients with other viral diseases compared to healthy subjects. Moreover, subgroup analysis of ACE2 expression as soluble and membrane-bound ACE2 revealed a remarkable increase in membrane-bound ACE2 in CVD patients, patients with viral infection compared to soluble ACE2 and pooled standard mean difference (SMD) with the random-effects model was 0.37 and 2.23 respectively. CONCLUSION It was observed that utilizing the ACE2 by SARS-CoV2 for its entry and its consequence leads to several complications. So there is a need to investigate the underlying mechanism along with novel therapeutic strategies.
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Affiliation(s)
- Dipanjali Dhananjay Kamthe
- Department of Pharmacology, STES's, Smt. Kashibai Navale College of PharmacySavitribai Phule Pune UniversityPuneIndia
| | - Swapnil Dilip Sarangkar
- Department of Pharmacology, STES's, Smt. Kashibai Navale College of PharmacySavitribai Phule Pune UniversityPuneIndia
| | - Manali Suresh Dalvi
- Department of Pharmacology, STES's, Smt. Kashibai Navale College of PharmacySavitribai Phule Pune UniversityPuneIndia
| | - Netra Arun Gosavi
- Department of Pharmacology, STES's, Smt. Kashibai Navale College of PharmacySavitribai Phule Pune UniversityPuneIndia
| | - Vandana Sandeep Nikam
- Department of Pharmacology, STES's, Smt. Kashibai Navale College of PharmacySavitribai Phule Pune UniversityPuneIndia
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16
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Leowattana W, Leowattana T, Leowattana P. Circulating angiotensin converting enzyme 2 and COVID-19. World J Clin Cases 2022; 10:12470-12483. [PMID: 36579082 PMCID: PMC9791519 DOI: 10.12998/wjcc.v10.i34.12470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/20/2022] [Accepted: 11/08/2022] [Indexed: 12/02/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a widespread outbreak since December 2019. The SARS-CoV-2 infection-related illness has been dubbed the coronavirus disease 2019 (COVID-19) by the World Health Organization. Asymptomatic and subclinical infections, a severe hyper-inflammatory state, and mortality are all examples of clinical signs. After attaching to the angiotensin converting enzyme 2 (ACE2) receptor, the SARS-CoV-2 virus can enter cells through membrane fusion and endocytosis. In addition to enabling viruses to cling to target cells, the connection between the spike protein (S-protein) of SARS-CoV-2 and ACE2 may potentially impair the functionality of ACE2. Blood pressure is controlled by ACE2, which catalyzes the hydrolysis of the active vasoconstrictor octapeptide angiotensin (Ang) II to the heptapeptide Ang-(1-7) and free L-Phe. Additionally, Ang I can be broken down by ACE2 into Ang-(1-9) and metabolized into Ang-(1-7). Numerous studies have demonstrated that circulating ACE2 (cACE2) and Ang-(1-7) have the ability to restore myocardial damage in a variety of cardiovascular diseases and have anti-inflammatory, antioxidant, anti-apoptotic, and anti-cardiomyocyte fibrosis actions. There have been some suggestions for raising ACE2 expression in COVID-19 patients, which might be used as a target for the creation of novel treatment therapies. With regard to this, SARS-CoV-2 is neutralized by soluble recombinant human ACE2 (hrsACE2), which binds the viral S-protein and reduces damage to a variety of organs, including the heart, kidneys, and lungs, by lowering Ang II concentrations and enhancing conversion to Ang-(1-7). This review aims to investigate how the presence of SARS-CoV-2 and cACE2 are related. Additionally, there will be discussion of a number of potential therapeutic approaches to tip the ACE/ACE-2 balance in favor of the ACE-2/Ang-(1-7) axis.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Bangkok, Thailand
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17
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Devaux CA, Camoin-Jau L. An update on angiotensin-converting enzyme 2 structure/functions, polymorphism, and duplicitous nature in the pathophysiology of coronavirus disease 2019: Implications for vascular and coagulation disease associated with severe acute respiratory syndrome coronavirus infection. Front Microbiol 2022; 13:1042200. [PMID: 36519165 PMCID: PMC9742611 DOI: 10.3389/fmicb.2022.1042200] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/07/2022] [Indexed: 08/01/2023] Open
Abstract
It has been known for many years that the angiotensin-converting enzyme 2 (ACE2) is a cell surface enzyme involved in the regulation of blood pressure. More recently, it was proven that the severe acute respiratory syndrome coronavirus (SARS-CoV-2) interacts with ACE2 to enter susceptible human cells. This functional duality of ACE2 tends to explain why this molecule plays such an important role in the clinical manifestations of coronavirus disease 2019 (COVID-19). At the very start of the pandemic, a publication from our Institute (entitled "ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome"), was one of the first reviews linking COVID-19 to the duplicitous nature of ACE2. However, even given that COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin system (RAS), we were still far from understanding the complexity of the mechanisms which are controlled by ACE2 in different cell types. To gain insight into the physiopathology of SARS-CoV-2 infection, it is essential to consider the polymorphism and expression levels of the ACE2 gene (including its alternative isoforms). Over the past 2 years, an impressive amount of new results have come to shed light on the role of ACE2 in the pathophysiology of COVID-19, requiring us to update our analysis. Genetic linkage studies have been reported that highlight a relationship between ACE2 genetic variants and the risk of developing hypertension. Currently, many research efforts are being undertaken to understand the links between ACE2 polymorphism and the severity of COVID-19. In this review, we update the state of knowledge on the polymorphism of ACE2 and its consequences on the susceptibility of individuals to SARS-CoV-2. We also discuss the link between the increase of angiotensin II levels among SARS-CoV-2-infected patients and the development of a cytokine storm associated microvascular injury and obstructive thrombo-inflammatory syndrome, which represent the primary causes of severe forms of COVID-19 and lethality. Finally, we summarize the therapeutic strategies aimed at preventing the severe forms of COVID-19 that target ACE2. Changing paradigms may help improve patients' therapy.
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Affiliation(s)
- Christian A. Devaux
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Center National de la Recherche Scientifique, Marseille, France
| | - Laurence Camoin-Jau
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU–Méditerranée Infection, Marseille, France
- Laboratoire d’Hématologie, Hôpital de La Timone, APHM, Boulevard Jean-Moulin, Marseille, France
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18
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Wissing SI, Obeid R, Rädle-Hurst T, Rohrer T, Herr C, Schöpe J, Geisel J, Bals R, Abdul-Khaliq H. Concentrations of Soluble Angiotensin Converting Enzyme 2 (sACE2) in Children and Adults with and without COVID-19. J Clin Med 2022; 11:jcm11226799. [PMID: 36431276 PMCID: PMC9698605 DOI: 10.3390/jcm11226799] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/29/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, leads to illness and death. Various risk factors for a severe course, such as higher age, male gender and pre-existing illnesses are known. However, pathophysiological risk factors are largely unclear. Notably, the mild course of disease in children is conspicuous. Angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2 and is a key enzyme in infection. Differences in the distribution of ACE2 can provide insights into different courses of COVID-19. Our aim was to elucidate the role of ACE2 as a pathophysiological risk factor by measuring soluble ACE2 (sACE2) via ELISA in blood samples (lithium-heparin-plasma or serum) of 367 individuals including children and adults with and without COVID-19. sACE2-levels were compared between the groups according to age and sex. In adults and children with COVID-19, sACE2-concentrations are significantly higher compared to healthy individuals. sACE2-levels increase with age and are lower in children compared to adults with COVID-19. Sex doesn't significantly influence sACE2-concentration. It remains unclear whether sACE2 concentrations increase because of the infection and what factors could influence this response. In conclusion, the increase of sACE2-concentration with age could indicate that ACE2 concentrations mirror increased COVID-19 severity.
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Affiliation(s)
- Sarah Isabella Wissing
- Department of Pediatric Cardiology, Saarland University Hospital, 66421 Homburg, Germany
| | - Rima Obeid
- Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, 66421 Homburg, Germany
| | - Tanja Rädle-Hurst
- Department of Pediatric Cardiology, Saarland University Hospital, 66421 Homburg, Germany
| | - Tilman Rohrer
- Department of Pediatric Endocrinology, Saarland University Hospital, 66421 Homburg, Germany
| | - Christian Herr
- Department of Internal Medicine V–Pulmonology, Allergology and Critical Care Medicine, Saarland University Hospital, 66421 Homburg, Germany
| | - Jakob Schöpe
- Institute for Medical Biometry, Epidemiology and Medical Informatics, Saarland University Medical Center, 66421 Homburg, Germany
| | - Jürgen Geisel
- Department of Clinical Chemistry and Laboratory Medicine, Saarland University Hospital, 66421 Homburg, Germany
| | - Robert Bals
- Department of Internal Medicine V–Pulmonology, Allergology and Critical Care Medicine, Saarland University Hospital, 66421 Homburg, Germany
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University Campus, 66123 Saarbrücken, Germany
| | - Hashim Abdul-Khaliq
- Department of Pediatric Cardiology, Saarland University Hospital, 66421 Homburg, Germany
- Correspondence: ; Tel.: +49-6841-1628306
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19
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Spilias N, Martyn T, Denby KJ, Harb SC, Popovic ZB, Kapadia SR. Left Ventricular Systolic Dysfunction in Aortic Stenosis: Pathophysiology, Diagnosis, Management, and Future Directions. STRUCTURAL HEART : THE JOURNAL OF THE HEART TEAM 2022; 6:100089. [PMID: 37288060 PMCID: PMC10242576 DOI: 10.1016/j.shj.2022.100089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 06/09/2023]
Abstract
Degenerative calcific aortic stenosis (AS) is the most common valvular heart disease and often co-exists with left ventricular (LV) systolic dysfunction at the time of diagnosis. Impaired LV systolic function has been associated with worse outcomes in the setting of AS, even after successful aortic valve replacement (AVR). Myocyte apoptosis and myocardial fibrosis are the 2 key mechanisms responsible for the transition from the initial adaptation phase of LV hypertrophy to the phase of heart failure with reduced ejection fraction. Novel advanced imaging methods, based on echocardiography and cardiac magnetic resonance imaging, can detect LV dysfunction and remodeling at an early and reversible stage, with important implications for the optimal timing of AVR especially in patients with asymptomatic severe AS. Furthermore, the advent of transcatheter AVR as a first-line treatment for AS with excellent procedural outcomes, and evidence that even moderate AS portends worse prognosis in heart failure with reduced ejection fraction patients, has raised the question of early valve intervention in this patient population. With this review, we describe the pathophysiology and outcomes of LV systolic dysfunction in the setting of AS, present imaging predictors of LV recovery after AVR, and discuss future directions in the treatment of AS extending beyond the traditional indications defined in the current guidelines.
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Affiliation(s)
| | | | | | | | | | - Samir R. Kapadia
- Address correspondence to: Samir Kapadia, MD, Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Mail Code J2-3, 9500 Euclid Ave, Cleveland, OH 44195.
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20
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Louisa M, Cahyadi D, Nilasari D, Soetikno V. Lack of Correlation Between Soluble Angiotensin-Converting Enzyme 2 and Inflammatory Markers in Hospitalized COVID-19 Patients with Hypertension. Infect Drug Resist 2022; 15:4799-4807. [PMID: 36045873 PMCID: PMC9420737 DOI: 10.2147/idr.s369771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/10/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose This study aimed to investigate the correlation of plasma soluble angiotensin-converting enzyme 2, sACE2, and several inflammatory markers in COVID-19 patients requiring hospitalization with hypertension. Additionally, we analyzed the effects of renin-angiotensin-aldosterone-system, RAAS, inhibitors on the levels of sACE2 and inflammatory marker levels in patients with COVID-19. Patients and Methods This cross-sectional study involved patients with COVID-19 who required hospitalization on a stable dose of antihypertensive drugs. The study included three hospitals in Jakarta and Tangerang, Indonesia, between December 2020 and June 2021. We classified eligible subjects into two groups: patients with COVID-19 treated with antihypertensive RAAS inhibitors or non-RAAS inhibitors. Results We found no correlation between sACE2 and all the inflammatory and coagulation markers studied (high-sensitivity C-reactive protein, IL-6, IL-10, IL6/IL10, tumor necrosis factor-α, neutrophil-to-lymphocyte ratio, and D-dimer) in COVID-19 patients with hypertension. Further analysis showed lower sACE2 concentrations and IL-6/IL-10 ratio in patients treated with RAAS inhibitors vs those treated with non-RAAS inhibitors. Conclusion We found no correlation between ACE2 and inflammatory markers. Using RAAS inhibitors resulted in a lower sACE2 and IL-6/IL-10 ratio. The type of antihypertensive treatments has a neutral effect on disease severity and outcome in COVID-19 patients with hypertension. However, to firmly-established these effects, our findings should be confirmed in a much larger population.
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Affiliation(s)
- Melva Louisa
- Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Daniel Cahyadi
- Master Program in Biomedical Sciences, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Dina Nilasari
- Department of Clinical Research, Siloam Hospitals, Jakarta, Indonesia.,Faculty of Medicine, University of Hasanuddin, Makassar, South Sulawesi, Indonesia
| | - Vivian Soetikno
- Department of Pharmacology and Therapeutics, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
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21
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Govender N, Khaliq O, Moodley J, Naicker T. Unravelling the Mechanistic Role of ACE2 and TMPRSS2 in Hypertension: A Risk Factor for COVID-19. Curr Hypertens Rev 2022; 18:130-137. [PMID: 36508271 DOI: 10.2174/1573402118666220816090809] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND This review explores the mechanistic action of angiotensin-converting enzyme- 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the renin-angiotensinaldosterone system (RAAS) that predisposes hypertensive patients to the adverse outcome of severe COVID-19. METHODS AND RESULTS Entry of SARS-CoV-2 into the host cell via ACE2 disrupts the RAAS system, creating an imbalance between ACE and ACE2, with an increased inflammatory response, leading to hypertension (HTN), pulmonary vasoconstriction and acute respiratory distress. SARSCoV- 2 may also predispose infected individuals with existing HTN to a greater risk of severe COVID-19 complications. In the duality of COVID-19 and HTN, the imbalance of ACE and ACE2 results in an elevation of AngII and a decrease in Ang (1-7), a hyperinflammatory response and endothelial dysfunction. Endothelial dysfunction is the main factor predisposing hypertensive patients to severe COVID-19 and vice-versa. CONCLUSION Despite the increase in ACE2 expression in hypertensive SARS-CoV-2 infected patients, ARBs/ACE inhibitors do not influence their severity and clinical outcomes, implicating continued usage. Future large-scale clinical trials are warranted to further elucidate the association between HTN and SARS-CoV-2 infection and the use of ARBs/ACEIs in SARS-CoV-2 hypertensive patients.
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Affiliation(s)
- Nalini Govender
- Department of Basic Medical Sciences, Faculty of Health Sciences, Durban University of Technology, Durban 4001, South Africa
| | - Olive Khaliq
- The Department of Paediatrics and Child Health, Faculty of Health Sciences, The University of the Free State, Bloemfontein 9300, South Africa
| | - Jagidesa Moodley
- Women's Health and HIV Research Group, Department of Obstetrics and Gynaecology, School of Clinical Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
| | - Thajasvarie Naicker
- Optics & Imaging Centre, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
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22
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Xue F, Cheng J, Liu Y, Cheng C, Zhang M, Sui W, Chen W, Hao P, Zhang Y, Zhang C. Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice. Signal Transduct Target Ther 2022; 7:259. [PMID: 35909160 PMCID: PMC9339545 DOI: 10.1038/s41392-022-01054-3] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 05/06/2022] [Accepted: 06/05/2022] [Indexed: 02/08/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17fl/fl control, A17α-MHCKO control, ADAM17fl/fl diabetic and A17α-MHCKO diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17α-MHCKO and ADAM17fl/fl diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM.
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Affiliation(s)
- Fei Xue
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jing Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yanping Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Cheng Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Meng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wenhai Sui
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Wenqiang Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Panpan Hao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| | - Yun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Cheng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
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23
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Lim HY, Burrell LM, Brook R, Nandurkar HH, Donnan G, Ho P. The Need for Individualized Risk Assessment in Cardiovascular Disease. J Pers Med 2022; 12:jpm12071140. [PMID: 35887637 PMCID: PMC9323107 DOI: 10.3390/jpm12071140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular disease remains the leading cause of death in the era of modern medicine despite major advancements in this field. Current available clinical surrogate markers and blood tests do not adequately predict individual risk of cardiovascular disease. A more precise and sophisticated tool that can reliably predict the thrombosis and bleeding risks at an individual level is required in order for clinicians to confidently recommend early interventions with a favorable risk–benefit profile. Critical to the development of this tool is the assessment and understanding of Virchow’s triad and its complex interactions between hypercoagulability, endothelial dysfunction and vessel flow, a fundamental concept to the development of thrombosis. This review explores the pathophysiology of cardiovascular disease stemming from the triad of factors and how individualized risk assessment can be improved through the multimodal use of tools such as global coagulation assays, endothelial biomarkers and vessel flow assessment.
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Affiliation(s)
- Hui Yin Lim
- Northern Pathology Victoria, Northern Health, Epping, Melbourne, VIC 3076, Australia; (H.Y.L.); (R.B.)
- Department of Hematology, Northern Health, Epping, Melbourne, VIC 3076, Australia
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia;
- Department of Medicine, Northern Health, University of Melbourne, Epping, Melbourne, VIC 3076, Australia
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Melbourne, VIC 3084, Australia;
| | - Louise M. Burrell
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Melbourne, VIC 3084, Australia;
| | - Rowena Brook
- Northern Pathology Victoria, Northern Health, Epping, Melbourne, VIC 3076, Australia; (H.Y.L.); (R.B.)
- Department of Hematology, Northern Health, Epping, Melbourne, VIC 3076, Australia
| | - Harshal H. Nandurkar
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia;
| | - Geoffrey Donnan
- The Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia;
| | - Prahlad Ho
- Northern Pathology Victoria, Northern Health, Epping, Melbourne, VIC 3076, Australia; (H.Y.L.); (R.B.)
- Department of Hematology, Northern Health, Epping, Melbourne, VIC 3076, Australia
- Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia;
- Department of Medicine, Northern Health, University of Melbourne, Epping, Melbourne, VIC 3076, Australia
- Correspondence: ; Tel.: +613-8405-8480
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24
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McGill JR, Lagassé HAD, Hernandez N, Hopkins L, Jankowski W, McCormick Q, Simhadri V, Golding B, Sauna ZE. A structural homology approach to identify potential cross-reactive antibody responses following SARS-CoV-2 infection. Sci Rep 2022; 12:11388. [PMID: 35794133 PMCID: PMC9259575 DOI: 10.1038/s41598-022-15225-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/21/2022] [Indexed: 11/09/2022] Open
Abstract
The emergence of the novel SARS-CoV-2 virus is the most important public-health issue of our time. Understanding the diverse clinical presentations of the ensuing disease, COVID-19, remains a critical unmet need. Here we present a comprehensive listing of the diverse clinical indications associated with COVID-19. We explore the theory that anti-SARS-CoV-2 antibodies could cross-react with endogenous human proteins driving some of the pathologies associated with COVID-19. We describe a novel computational approach to estimate structural homology between SARS-CoV-2 proteins and human proteins. Antibodies are more likely to interrogate 3D-structural epitopes than continuous linear epitopes. This computational workflow identified 346 human proteins containing a domain with high structural homology to a SARS-CoV-2 Wuhan strain protein. Of these, 102 proteins exhibit functions that could contribute to COVID-19 clinical pathologies. We present a testable hypothesis to delineate unexplained clinical observations vis-à-vis COVID-19 and a tool to evaluate the safety-risk profile of potential COVID-19 therapies.
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Affiliation(s)
- Joseph R McGill
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - H A Daniel Lagassé
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Nancy Hernandez
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Louis Hopkins
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Wojciech Jankowski
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Quinn McCormick
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Vijaya Simhadri
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Basil Golding
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Zuben E Sauna
- Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
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25
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The Effect of Renin-Angiotensin Blockers on COVID-19 Related Mortality: A Tertiary Center's Experience. COR ET VASA 2022. [DOI: 10.33678/cor.2021.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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26
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Yang Y, Yan M. Mechanisms of Cardiovascular System Injury Induced by COVID-19 in Elderly Patients With Cardiovascular History. Front Cardiovasc Med 2022; 9:859505. [PMID: 35600485 PMCID: PMC9116509 DOI: 10.3389/fcvm.2022.859505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
The coronavirus disease-2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), represents a great threat to healthcare and socioeconomics worldwide. In addition to respiratory manifestations, COVID-19 promotes cardiac injuries, particularly in elderly patients with cardiovascular history, leading to a higher risk of progression to critical conditions. The SARS-CoV-2 infection is initiated as virus binding to angiotensin-converting enzyme 2 (ACE2), which is highly expressed in the heart, resulting in direct infection and dysregulation of the renin-angiotensin system (RAS). Meanwhile, immune response and hyper-inflammation, as well as endothelial dysfunction and thrombosis implicate in COVID-19 infection. Herein, we provide an overview of the proposed mechanisms of cardiovascular injuries in COVID-19, particularly in elderly patients with pre-existing cardiovascular diseases, aiming to set appropriate management and improve their clinical outcomes.
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27
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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.
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28
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Soós B, Fagyas M, Horváth Á, Végh E, Pusztai A, Czókolyová M, Csongrádi A, Hamar A, Pethő Z, Bodnár N, Kerekes G, Hodosi K, Szekanecz É, Szamosi S, Szántó S, Szűcs G, Papp Z, Szekanecz Z. Angiotensin Converting Enzyme Activity in Anti-TNF-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients. Front Med (Lausanne) 2022; 8:785744. [PMID: 35155468 PMCID: PMC8828652 DOI: 10.3389/fmed.2021.785744] [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] [Received: 09/29/2021] [Accepted: 12/10/2021] [Indexed: 11/28/2022] Open
Abstract
Introduction Angiotensin-converting enzyme (ACE) and ACE2 have been implicated in the regulation of vascular physiology. Elevated synovial and decreased or normal ACE or ACE2 levels have been found in rheumatoid arthritis (RA). Very little is known about the effects of tumor necrosis factor α (TNF-α) inhibition on ACE or ACE2 homeostasis. In this study, we assessed the effects of one-year anti-TNF therapy on ACE and ACE2 production in RA and ankylosing spondylitis (AS) in association with other biomarkers. Patients and Methods Forty patients including 24 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 16 AS patients treated with ETN were included in a 12-month follow-up study. Serum ACE levels were determined by commercial ELISA, while serum ACE2 activity was assessed using a specific quenched fluorescent substrate. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. In addition, CRP, rheumatoid factor (RF) and ACPA were also measured. All assessments were performed at baseline and 6 and 12 months after treatment initiation. Results Anti-TNF therapy increased ACE levels in the full cohort, as well as in the RA and AS subsets. ACE2 activity increased in the full cohort, while the ACE/ACE2 ratio increased in the full cohort and in the RA subset (p < 0.05). Uni- and multivariable regression analyses determined associations between ACE or ACE/ACE2 ratios at different time points and disease duration, CRP, RF, FMD and IMT (p < 0.05). ACE2 activity correlated with CRP. The changes of ACE or ACE2 over 12 months were determined by treatment together with either RF or FMD (p < 0.05). Conclusions Anti-TNF treatment may increase ACE and ACE2 in the sera of RA and AS patients. ACE and ACE2 may be associated with disease duration, markers of inflammation and vascular pathophysiology. The effects of TNF inhibition on ACE and ACE2 may reflect, in part, the effects of these biologics on the cardiovascular system.
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Affiliation(s)
- Boglárka Soós
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Miklós Fagyas
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ágnes Horváth
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Edit Végh
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Anita Pusztai
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Monika Czókolyová
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Alexandra Csongrádi
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Hamar
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zsófia Pethő
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Nóra Bodnár
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - György Kerekes
- Intensive Care Unit, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Katalin Hodosi
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Éva Szekanecz
- Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Szilvia Szamosi
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Sándor Szántó
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.,Department of Sports Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Gabriella Szűcs
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Papp
- Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Zoltán Szekanecz
- Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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29
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Zhang G, Brown JS, Quartararo AJ, Li C, Tan X, Hanna S, Antilla S, Cowfer AE, Loas A, Pentelute BL. Rapid de novo discovery of peptidomimetic affinity reagents for human angiotensin converting enzyme 2. Commun Chem 2022; 5:8. [PMID: 36697587 PMCID: PMC9814530 DOI: 10.1038/s42004-022-00625-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/23/2021] [Indexed: 01/28/2023] Open
Abstract
Rapid discovery and development of serum-stable, selective, and high affinity peptide-based binders to protein targets are challenging. Angiotensin converting enzyme 2 (ACE2) has recently been identified as a cardiovascular disease biomarker and the primary receptor utilized by the severe acute respiratory syndrome coronavirus 2. In this study, we report the discovery of high affinity peptidomimetic binders to ACE2 via affinity selection-mass spectrometry (AS-MS). Multiple high affinity ACE2-binding peptides (ABP) were identified by selection from canonical and noncanonical peptidomimetic libraries containing 200 million members (dissociation constant, KD = 19-123 nM). The most potent noncanonical ACE2 peptide binder, ABP N1 (KD = 19 nM), showed enhanced serum stability in comparison with the most potent canonical binder, ABP C7 (KD = 26 nM). Picomolar to low nanomolar ACE2 concentrations in human serum were detected selectively using ABP N1 in an enzyme-linked immunosorbent assay. The discovery of serum-stable noncanonical peptidomimetics like ABP N1 from a single-pass selection demonstrates the utility of advanced AS-MS for accelerated development of affinity reagents to protein targets.
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Affiliation(s)
- Genwei Zhang
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Joseph S. Brown
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Anthony J. Quartararo
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA ,Present Address: FogPharma, 30 Acorn Park Dr, Cambridge, MA 02140 USA
| | - Chengxi Li
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Xuyu Tan
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Stephanie Hanna
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Sarah Antilla
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Amanda E. Cowfer
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Andrei Loas
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA
| | - Bradley L. Pentelute
- grid.116068.80000 0001 2341 2786Massachusetts Institute of Technology, Department of Chemistry, 77 Massachusetts Avenue, Cambridge, MA 02139 USA ,grid.116068.80000 0001 2341 2786The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02142 USA ,grid.116068.80000 0001 2341 2786Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139 USA ,grid.66859.340000 0004 0546 1623Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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30
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García-Escobar A, Vera-Vera S, Jurado-Román A, Jiménez-Valero S, Galeote G, Moreno R. Calcium Signaling Pathway Is Involved in the Shedding of ACE2 Catalytic Ectodomain: New Insights for Clinical and Therapeutic Applications of ACE2 for COVID-19. Biomolecules 2022; 12:biom12010076. [PMID: 35053224 PMCID: PMC8774087 DOI: 10.3390/biom12010076] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/26/2021] [Accepted: 12/29/2021] [Indexed: 02/04/2023] Open
Abstract
The angiotensin-converting enzyme 2 (ACE2) is a type I integral membrane that exists in two forms: the first is a transmembrane protein; the second is a soluble catalytic ectodomain of ACE2. The catalytic ectodomain of ACE2 undergoes shedding by a disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), in which calmodulin mediates the calcium signaling pathway that is involved in ACE2 release, resulting in a soluble catalytic ectodomain of ACE2 that can be measured as soluble ACE2 plasma activity. The shedding of the ACE2 catalytic ectodomain plays a role in cardiac remodeling and endothelial dysfunction and is a predictor of all-cause mortality, including cardiovascular mortality. Moreover, considerable evidence supports that the ACE2 catalytic ectodomain is an essential entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Additionally, endotoxins and the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-alpha (TNFα) all enhanced soluble catalytic ectodomain ACE2 shedding from the airway epithelia, suggesting that the shedding of ACE2 may represent a mechanism by which viral entry and infection may be controlled such as some types of betacoronavirus. In this regard, ACE2 plays an important role in inflammation and thrombotic response, and its down-regulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury. Soluble forms of ACE2 have recently been shown to inhibit SARS-CoV-2 infection. Furthermore, given that vitamin D enhanced the shedding of ACE2, some studies reported that vitamin D treatment is associated with prognosis improvement in COVID-19. This is an updated review on the evidence, clinical, and therapeutic applications of ACE2 for COVID-19.
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Affiliation(s)
- Artemio García-Escobar
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-917-27-70-00
| | - Silvio Vera-Vera
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alfonso Jurado-Román
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Santiago Jiménez-Valero
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Guillermo Galeote
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Raúl Moreno
- Cardiology Department, Interventional Cardiology Section, University Hospital La Paz, 28046 Madrid, Spain; (S.V.-V.); (A.J.-R.); (S.J.-V.); (G.G.); (R.M.)
- Instituto de Investigación Hospital La Paz (IDIPAZ), 28029 Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
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31
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Islam MT, Quispe C, Martorell M, Docea AO, Salehi B, Calina D, Reiner Ž, Sharifi-Rad J. Dietary supplements, vitamins and minerals as potential interventions against viruses: Perspectives for COVID-19. INT J VITAM NUTR RES 2022; 92:49-66. [PMID: 33435749 DOI: 10.1024/0300-9831/a000694] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The novel coronavirus (SARS-CoV-2) causing COVID-19 disease pandemic has infected millions of people and caused more than thousands of deaths in many countries across the world. The number of infected cases is increasing day by day. Unfortunately, we do not have a vaccine and specific treatment for it. Along with the protective measures, respiratory and/or circulatory supports and some antiviral and retroviral drugs have been used against SARS-CoV-2, but there are no more extensive studies proving their efficacy. In this study, the latest publications in the field have been reviewed, focusing on the modulatory effects on the immunity of some natural antiviral dietary supplements, vitamins and minerals. Findings suggest that several dietary supplements, including black seeds, garlic, ginger, cranberry, orange, omega-3 and -6 polyunsaturated fatty acids, vitamins (e.g., A, B vitamins, C, D, E), and minerals (e.g., Cu, Fe, Mg, Mn, Na, Se, Zn) have anti-viral effects. Many of them act against various species of respiratory viruses, including severe acute respiratory syndrome-related coronaviruses. Therefore, dietary supplements, including vitamins and minerals, probiotics as well as individual nutritional behaviour can be used as adjuvant therapy together with antiviral medicines in the management of COVID-19 disease.
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Affiliation(s)
- Muhammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Bangladesh
| | - Cristina Quispe
- Facultad de Ciencias de la Salud, Universidad Arturo Prat, Chile
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, Concepción, Chile
- Universidad de Concepción, Unidad de Desarrollo Tecnológico (UDT), Concepción, Chile
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, Romania
| | - Bahare Salehi
- Medical Ethics and Law Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Romania
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Croatia
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
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32
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Hussain M, Collier P, Moudgil R. Cardiovascular Complications in Major 21st Century Viral Epidemics and Pandemics: an Insight into COVID-19. Curr Cardiol Rev 2021; 17:e051121192897. [PMID: 33874873 PMCID: PMC8950501 DOI: 10.2174/1573403x17666210419113037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/23/2021] [Accepted: 02/24/2021] [Indexed: 12/30/2022] Open
Abstract
There have many major history-defining epidemics and pandemics in the 21st century. It is well known that acute infections can cause cardiovascular (CV) complications, especially in those with underlying cardiac disease. The variation in rates and types of CVD complications in major 21st century epidemics and pandemics varies greatly. The coronavirus disease 2019 (COVID-19) pandemic has caused the turmoil of the century and has COVID-19 has resulted in substantial human and economic loss. The novelty of COVID-19 and emerging CV effects is a new entity. In this review, we discuss the major epidemics and pandemics of the 21st century and associated CVD complications.
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Affiliation(s)
- Muzna Hussain
- Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA,Address correspondence to this author at the Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA; Tel: (216) 445-6546, Fax: (216) 445- 6159; E-mail:
| | - Patrick Collier
- Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - Rohit Moudgil
- Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA
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33
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Sex differences in the lung ACE/ACE2 balance in hypertensive rats. Biosci Rep 2021; 41:230188. [PMID: 34751382 PMCID: PMC8655502 DOI: 10.1042/bsr20211201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 02/08/2023] Open
Abstract
The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 ± 17 vs. 43 ± 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).
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Almengló C, Couselo-Seijas M, Agra RM, Varela-Román A, García-Acuña JM, González-Peteiro M, González-Juanatey JR, Eiras S, Álvarez E. Soluble angiotensin-converting enzyme levels in heart failure or acute coronary syndrome: revisiting its modulation and prognosis value. J Mol Med (Berl) 2021; 99:1741-1753. [PMID: 34529122 PMCID: PMC8443916 DOI: 10.1007/s00109-021-02129-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/21/2021] [Accepted: 08/09/2021] [Indexed: 11/30/2022]
Abstract
The main objective was to compare the meaning of soluble angiotensin-converting enzyme-2 (sACE2) plasma levels modulation on the prognosis of two cohorts of heart failure (HF) and acute coronary syndrome (ACS). We conducted an observational clinical study where sACE2 was measured in two cohorts of HF or ACS (102 patients each), matched by age and gender. The primary endpoint (cardiac death) and the secondary endpoints (non-fatal myocardial infarction or HF readmission) were registered during a 5-year follow-up period. Association with pharmacotherapy was studied, and the effects of cardiovascular drugs on ACE isoforms expression were analysed in human umbilical vein endothelial cells (HUVEC) in vitro. The levels of sACE2 were significantly higher in the HF than ACS cohort. sACE2 was inversely related with the leukocytes number and directly with urea levels. In the ACS cohort, sACE2 was associated with age and glycaemic parameters, but in the HF cohort, the association was with N-terminal pro-B-type natriuretic peptide. The levels of sACE2 were related to long-term prognosis and confirmed as a non-independent predictor in the HF cohort. Soluble ACE2 was higher in patients treated with angiotensin receptors blockers and β-blockers, accordingly with losartan and metoprolol upregulation of ACE1 and ACE2 in HUVECs. Plasma levels of sACE2 were higher in HF than in ACS, independently of age and gender, and were related to long-term cardiac death in the HF cohort. Losartan and metoprolol, but not enalapril, upregulated ACE expression in endothelial cells, accordingly with higher levels of sACE2 in patients using these drugs.
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Affiliation(s)
- Cristina Almengló
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
| | - Marinela Couselo-Seijas
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
| | - Rosa M Agra
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
- CIBERCV, Madrid, Spain
- Servicio de Cardiología y Unidad de Hemodinámica, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
| | - Alfonso Varela-Román
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
- CIBERCV, Madrid, Spain
- Servicio de Cardiología y Unidad de Hemodinámica, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
| | - José M García-Acuña
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
- CIBERCV, Madrid, Spain
- Servicio de Cardiología y Unidad de Hemodinámica, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
| | - Mercedes González-Peteiro
- Departamento de Enfermería, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain
| | - José R González-Juanatey
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
- CIBERCV, Madrid, Spain
- Servicio de Cardiología y Unidad de Hemodinámica, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
| | - Sonia Eiras
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain
- CIBERCV, Madrid, Spain
| | - Ezequiel Álvarez
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Travesía da Choupana S/N, 15706, Santiago de Compostela, A Coruña, Spain.
- CIBERCV, Madrid, Spain.
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, A Coruña, Spain.
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Castiglione GM, Zhou L, Xu Z, Neiman Z, Hung CF, Duh EJ. Evolutionary pathways to SARS-CoV-2 resistance are opened and closed by epistasis acting on ACE2. PLoS Biol 2021; 19:e3001510. [PMID: 34932561 PMCID: PMC8730403 DOI: 10.1371/journal.pbio.3001510] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 01/05/2022] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects a broader range of mammalian species than previously predicted, binding a diversity of angiotensin converting enzyme 2 (ACE2) orthologs despite extensive sequence divergence. Within this sequence degeneracy, we identify a rare sequence combination capable of conferring SARS-CoV-2 resistance. We demonstrate that this sequence was likely unattainable during human evolution due to deleterious effects on ACE2 carboxypeptidase activity, which has vasodilatory and cardioprotective functions in vivo. Across the 25 ACE2 sites implicated in viral binding, we identify 6 amino acid substitutions unique to mouse-one of the only known mammalian species resistant to SARS-CoV-2. Substituting human variants at these positions is sufficient to confer binding of the SARS-CoV-2 S protein to mouse ACE2, facilitating cellular infection. Conversely, substituting mouse variants into either human or dog ACE2 abolishes viral binding, diminishing cellular infection. However, these same substitutions decrease human ACE2 activity by 50% and are predicted as pathogenic, consistent with the extreme rarity of human polymorphisms at these sites. This trade-off can be avoided, however, depending on genetic background; if substituted simultaneously, these same mutations have no deleterious effect on dog ACE2 nor that of the rodent ancestor estimated to exist 70 million years ago. This genetic contingency (epistasis) may have therefore opened the road to resistance for some species, while making humans susceptible to viruses that use these ACE2 surfaces for binding, as does SARS-CoV-2.
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Affiliation(s)
- Gianni M. Castiglione
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Lingli Zhou
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Zhenhua Xu
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Zachary Neiman
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Chien-Fu Hung
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Elia J. Duh
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
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36
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Wang K, Gheblawi M, Nikhanj A, Munan M, MacIntyre E, O'Neil C, Poglitsch M, Colombo D, Del Nonno F, Kassiri Z, Sligl W, Oudit GY. Dysregulation of ACE (Angiotensin-Converting Enzyme)-2 and Renin-Angiotensin Peptides in SARS-CoV-2 Mediated Mortality and End-Organ Injuries. Hypertension 2021; 79:365-378. [PMID: 34844421 DOI: 10.1161/hypertensionaha.121.18295] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52-74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1-7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.
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Affiliation(s)
- Kaiming Wang
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.(K.W., A.N., G.Y.O.).,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. (K.W., M.G., A.N., G.Y.O.)
| | - Mahmoud Gheblawi
- Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. (K.W., M.G., A.N., G.Y.O.).,Department of Physiology, University of Alberta, Edmonton, Canada. (M.G., Z.K., G.Y.O.)
| | - Anish Nikhanj
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.(K.W., A.N., G.Y.O.).,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. (K.W., M.G., A.N., G.Y.O.)
| | - Matt Munan
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada. (M.M., E.M., W.S.)
| | - Erika MacIntyre
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada. (M.M., E.M., W.S.).,Division of Respirology, Department of Medicine, University of Alberta, Edmonton, Canada. (E.M.)
| | - Conar O'Neil
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada. (C.O., W.S.)
| | | | - Daniele Colombo
- Pathology Unit, National Institute for Infectious Diseases "Lazzaro Spallanzani," IRCCS, Rome, Italy (D.C., F.D.N.)
| | - Franca Del Nonno
- Pathology Unit, National Institute for Infectious Diseases "Lazzaro Spallanzani," IRCCS, Rome, Italy (D.C., F.D.N.)
| | - Zamaneh Kassiri
- Department of Physiology, University of Alberta, Edmonton, Canada. (M.G., Z.K., G.Y.O.)
| | - Wendy Sligl
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada. (M.M., E.M., W.S.).,Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada. (C.O., W.S.)
| | - Gavin Y Oudit
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Canada.(K.W., A.N., G.Y.O.).,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada. (K.W., M.G., A.N., G.Y.O.).,Department of Physiology, University of Alberta, Edmonton, Canada. (M.G., Z.K., G.Y.O.)
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37
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Feng F, Chen J, Zhao J, Li Y, Li M, Sun C. Killing Two Birds with One Stone by Administration of Soluble ACE2: A Promising Strategy to Treat Both Cardiovascular Diseases and SARS-CoV-2 Infection. Viruses 2021; 13:2243. [PMID: 34835049 PMCID: PMC8622942 DOI: 10.3390/v13112243] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 10/31/2021] [Accepted: 11/02/2021] [Indexed: 12/19/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells mainly by the angiotensin converting enzyme 2 (ACE2) receptor, which can recognize the spike (S) protein by its extracellular domain. Previously, recombinant soluble ACE2 (sACE2) has been clinically used as a therapeutic treatment for cardiovascular diseases. Recent data demonstrated that sACE2 can also be exploited as a decoy to effectively inhibit the cell entry of SARS-CoV-2, through blocking SARS-CoV-2 binding to membrane-anchored ACE2. In this study, we summarized the current findings on the optimized sACE2-based strategies as a therapeutic agent, including Fc fusion to prolong the half-life of sACE2, deep mutagenesis to create high-affinity decoys for SARS-CoV-2, or designing the truncated functional fragments to enhance its safety, among others. Considering that COVID-19 patients are often accompanied by manifestations of cardiovascular complications, we think that administration of sACE2 in COVID-19 patients may be a promising therapeutic strategy to simultaneously treat both cardiovascular diseases and SARS-CoV-2 infection. This review would provide insights for the development of novel therapeutic agents against the COVID-19 pandemic.
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Affiliation(s)
- Fengling Feng
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Jiaoshan Chen
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Jin Zhao
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Yanjun Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Minchao Li
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
| | - Caijun Sun
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (F.F.); (J.C.); (J.Z.); (Y.L.); (M.L.)
- Key Laboratory of Tropical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China
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38
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Higashikuni Y, Liu W, Obana T, Sata M. Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19: Current Findings and Therapeutic Implications. Int J Mol Sci 2021; 22:ijms222112081. [PMID: 34769508 PMCID: PMC8584434 DOI: 10.3390/ijms222112081] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with a great impact on social and economic activities, as well as public health. In most patients, the symptoms of COVID-19 are a high-grade fever and a dry cough, and spontaneously resolve within ten days. However, in severe cases, COVID-19 leads to atypical bilateral interstitial pneumonia, acute respiratory distress syndrome, and systemic thromboembolism, resulting in multiple organ failure with high mortality and morbidity. SARS-CoV-2 has immune evasion mechanisms, including inhibition of interferon signaling and suppression of T cell and B cell responses. SARS-CoV-2 infection directly and indirectly causes dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction, which interact with each other and are exacerbated by cardiovascular risk factors. In this review, we summarize current knowledge on the pathogenic basis of thromboinflammation and endothelial injury in COVID-19. We highlight the distinct contributions of dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction to the pathogenesis of COVID-19. In addition, we discuss potential therapeutic strategies targeting these mechanisms.
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Affiliation(s)
- Yasutomi Higashikuni
- Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (W.L.); (T.O.)
- Correspondence: (Y.H.); (M.S.)
| | - Wenhao Liu
- Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (W.L.); (T.O.)
| | - Takumi Obana
- Department of Cardiovascular Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (W.L.); (T.O.)
| | - Masataka Sata
- Department of Cardiovascular Medicine, The University of Tokushima, Tokushima 770-8503, Japan
- Correspondence: (Y.H.); (M.S.)
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39
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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.
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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
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40
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Gutiérrez-Chamorro L, Riveira-Muñoz E, Barrios C, Palau V, Nevot M, Pedreño-López S, Senserrich J, Massanella M, Clotet B, Cabrera C, Mitjà O, Crespo M, Pascual J, Riera M, Ballana E. SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients. Viruses 2021; 13:v13091715. [PMID: 34578296 PMCID: PMC8471465 DOI: 10.3390/v13091715] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/11/2022] Open
Abstract
Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-CoV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity.
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Affiliation(s)
- Lucía Gutiérrez-Chamorro
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
| | - Eva Riveira-Muñoz
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
| | - Clara Barrios
- Hospital del Mar Department of Nephrology, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; (C.B.); (V.P.); (M.C.); (J.P.)
| | - Vanesa Palau
- Hospital del Mar Department of Nephrology, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; (C.B.); (V.P.); (M.C.); (J.P.)
| | - Maria Nevot
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
| | - Sònia Pedreño-López
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
| | - Jordi Senserrich
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
| | - Marta Massanella
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
| | - Bonaventura Clotet
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
- Fight AIDS and Infectious Diseases Foundation, 08916 Badalona, Spain;
- Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
- Universitat Central de Catalunya, Universitat de Vic, 08500 Vic, Spain
| | - Cecilia Cabrera
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
| | - Oriol Mitjà
- Fight AIDS and Infectious Diseases Foundation, 08916 Badalona, Spain;
- Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain
- Universitat Central de Catalunya, Universitat de Vic, 08500 Vic, Spain
- Lihir Medical Centre-International SOS, Londolovit, Lihir Island, Papua New Guinea
| | - Marta Crespo
- Hospital del Mar Department of Nephrology, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; (C.B.); (V.P.); (M.C.); (J.P.)
| | - Julio Pascual
- Hospital del Mar Department of Nephrology, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; (C.B.); (V.P.); (M.C.); (J.P.)
| | - Marta Riera
- Hospital del Mar Department of Nephrology, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; (C.B.); (V.P.); (M.C.); (J.P.)
- Correspondence: (M.R.); (E.B.)
| | - Ester Ballana
- IrsiCaixa-AIDS Research Institute, Health Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, 08916 Badalona, Spain; (L.G.-C.); (E.R.-M.); (M.N.); (S.P.-L.); (J.S.); (M.M.); (B.C.); (C.C.)
- Correspondence: (M.R.); (E.B.)
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Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19? Adv Biol Regul 2021; 81:100820. [PMID: 34419773 PMCID: PMC8359569 DOI: 10.1016/j.jbior.2021.100820] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/05/2021] [Accepted: 08/09/2021] [Indexed: 12/15/2022]
Abstract
The article describes the possible pathophysiological origin of COVID-19 and the crucial role of renin-angiotensin system (RAS), providing several “converging” evidence in support of this hypothesis. SARS-CoV-2 has been shown to initially upregulate ACE2 systemic activity (early phase), which can subsequently induce compensatory responses leading to upregulation of both arms of the RAS (late phase) and consequently to critical, advanced and untreatable stages of COVID-19 disease. The main and initial actors of the process are ACE2 and ADAM17 zinc-metalloproteases, which, initially triggered by SARS-CoV-2 spike proteins, work together in increasing circulating Ang 1–7 and Ang 1–9 peptides and downstream (Mas and Angiotensin type 2 receptors) pathways with anti-inflammatory, hypotensive and antithrombotic activities. During the late phase of severe COVID-19, compensatory secretion of renin and ACE enzymes are subsequently upregulated, leading to inflammation, hypertension and thrombosis, which further sustain ACE2 and ADAM17 upregulation. Based on this hypothesis, COVID-19-phase-specific inhibition of different RAS enzymes is proposed as a pharmacological strategy against COVID-19 and vaccine-induced adverse effects. The aim is to prevent the establishment of positive feedback-loops, which can sustain hyperactivity of both arms of the RAS independently of viral trigger and, in some cases, may lead to Long-COVID syndrome.
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Gupta VK, Murthy MK, Patil S. Can Host Cell Proteins Like ACE2, ADAM17, TMPRSS2, Androgen Receptor be the Efficient Targets in SARS-CoV-2 Infection? Curr Drug Targets 2021; 22:1149-1157. [PMID: 33243116 DOI: 10.2174/1389450121999201125201112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/17/2020] [Accepted: 10/19/2020] [Indexed: 11/22/2022]
Abstract
A novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV- -2), which caused a large disease outbreak in Wuhan, China in December 2019, is currently spreading across the world. Along with binding of the virus spike with the host cell receptor, fusion of the viral envelope with host cell membranes is a critical step in establishing successful infection of SARS-CoV-2. In this entry process, a diversity of host cell proteases and androgen receptor play a very important role directly or indirectly. These features of SARS-CoV-2 entry contribute to its rapid spread and severe symptoms, high fatality rates among infected patients. This review is based on the latest published literature including review articles, research articles, hypothetical manuscript, preprint articles and official documents. The literature search was made from various published papers on physiological aspects relevant to SARS-CoV and SARS-CoV-2. In this report, we focus on the role of host cell proteases (ACE2, ADAM17, TMPRSS2) and androgen receptor (AR) in SARS-CoV-2 infection. The hypotheses put forth by us are based on the role played by the proteases ACE2, ADAM17, TMPRSS2 and AR in SARS-CoV-2 infection, which were deduced based on various studies. We have also summarized how these host proteins increase the pathology and the infective ability of SARS-CoV-2 and we posit that their inhibition may be a therapeutic option for preventing SARS-CoV-2 infection.
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Affiliation(s)
- Vivek K Gupta
- Department of Biochemistry, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra-282004, India
| | - Madhan K Murthy
- Department of Immunology, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra-282004, India
| | - Shripad Patil
- Department of Immunology, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra-282004, India
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Zanza C, Tassi MF, Romenskaya T, Piccolella F, Abenavoli L, Franceschi F, Piccioni A, Ojetti V, Saviano A, Canonico B, Montanari M, Zamai L, Artico M, Robba C, Racca F, Longhitano Y. Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019. Cells 2021; 10:1752. [PMID: 34359922 PMCID: PMC8306543 DOI: 10.3390/cells10071752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/21/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
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.
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Affiliation(s)
- Christian Zanza
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
- Foundation Ospedale Alba-Bra and Department of Anesthesia, Critical Care and Emergency Medicine, Pietro and Michele Ferrero Hospital, 12051 Verduno, Italy
| | - Michele Fidel Tassi
- Department of Emergency Medicine, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy;
| | - Tatsiana Romenskaya
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Fabio Piccolella
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy;
| | - Francesco Franceschi
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Andrea Piccioni
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Veronica Ojetti
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Angela Saviano
- Department of Emergency Medicine, Foundation of Policlinico Agostino Gemelli-IRCCS, Catholic University of Sacred Heart, 00168 Rome, Italy; (F.F.); (A.P.); (V.O.); (A.S.)
| | - Barbara Canonico
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
| | - Mariele Montanari
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
| | - Loris Zamai
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy; (B.C.); (M.M.); (L.Z.)
- National Institute for Nuclear Physics (INFN)-Gran Sasso National Laboratory (LNGS), 67100 Assergi L’Aquila, Italy
| | - Marco Artico
- Department of Sensory Organs, Sapienza University of Rome, 00185 Rome, Italy;
| | - Chiara Robba
- Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, 16132 Genoa, Italy;
| | - Fabrizio Racca
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
| | - Yaroslava Longhitano
- Department of Anesthesia and Critical Care, AON SS Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy; (T.R.); (F.P.); (F.R.); (Y.L.)
- Foundation Ospedale Alba-Bra and Department of Anesthesia, Critical Care and Emergency Medicine, Pietro and Michele Ferrero Hospital, 12051 Verduno, Italy
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Yalcin HC, Sukumaran V, Al-Ruweidi MKAA, Shurbaji S. Do Changes in ACE-2 Expression Affect SARS-CoV-2 Virulence and Related Complications: A Closer Look into Membrane-Bound and Soluble Forms. Int J Mol Sci 2021; 22:6703. [PMID: 34201415 PMCID: PMC8269184 DOI: 10.3390/ijms22136703] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 05/29/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, intestines, brain, and kidney, however, its functions in these organs are mostly unknown. ACE-2 has membrane-bound and soluble forms. Its expression levels are altered in disease states and by a variety of medications. Currently, it is not clear how altered ACE-2 levels influence ACE-2 virulence and relevant complications. In addition, membrane-bound and soluble forms are thought to have different effects. Most work on this topic in the literature is on the SARS-CoV virus that has a high genetic resemblance to SARS-Co-V-2 and also uses ACE-2 enzyme to enter the cell, but with much lower affinity. More recent studies on SARS-CoV-2 are mainly clinical studies aiming at relating the effect of medications that are thought to influence ACE-2 levels, with COVID-19 outcomes for patients under these medications. This review paper aims to summarize what is known about the relationship between ACE-2 levels and SARS-CoV/SARS-CoV-2 virulence under altered ACE-2 expression states.
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Affiliation(s)
- Huseyin C. Yalcin
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (M.K.A.A.A.-R.); (S.S.)
| | - Vijayakumar Sukumaran
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (M.K.A.A.A.-R.); (S.S.)
| | - Mahmoud Khatib A. A. Al-Ruweidi
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (M.K.A.A.A.-R.); (S.S.)
- Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha 2713, Qatar
| | - Samar Shurbaji
- Biomedical Research Center, Qatar University, Doha 2713, Qatar; (M.K.A.A.A.-R.); (S.S.)
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Liu LP, Zhang XL, Li J. New perspectives on angiotensin-converting enzyme 2 and its related diseases. World J Diabetes 2021; 12:839-854. [PMID: 34168732 PMCID: PMC8192247 DOI: 10.4239/wjd.v12.i6.839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/30/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Since the worldwide outbreak of coronavirus disease 2019, angiotensin-converting enzyme 2 (ACE2) has received widespread attention as the cell receptor of the severe acute respiratory syndrome coronavirus 2 virus. At the same time, as a key enzyme in the renin-angiotensin-system, ACE2 is considered to be an endogenous negative regulator of vasoconstriction, proliferation, fibrosis, and proinflammation caused by the ACE-angiotensin II-angiotensin type 1 receptor axis. ACE2 is now implicated as being closely connected to diabetes, cardiovascular, kidney, and lung diseases, and so on. This review covers the available information on the host factors regulating ACE2 and discusses its role in a variety of pathophysiological conditions in animal models and humans.
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Affiliation(s)
- Li-Ping Liu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Xiao-Li Zhang
- TheFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg 68135, Baden-Württemberg, Germany
| | - Jian Li
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
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Kragstrup TW, Singh HS, Grundberg I, Nielsen ALL, Rivellese F, Mehta A, Goldberg MB, Filbin MR, Qvist P, Bibby BM. Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients. PLoS One 2021; 16:e0252799. [PMID: 34086837 PMCID: PMC8177449 DOI: 10.1371/journal.pone.0252799] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/21/2021] [Indexed: 01/04/2023] Open
Abstract
AIMS Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). Here, we investigate associations between plasma ACE2 and outcome of COVID-19. METHODS AND RESULTS This analysis used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort). Comprehensive clinical data were collected on this cohort, including 28-day outcomes. The samples were run on the Olink® Explore 1536 platform which includes measurement of the ACE2 protein. High admission plasma ACE2 in COVID-19 patients was associated with increased maximal illness severity within 28 days with OR = 1.8, 95%-CI: 1.4-2.3 (P < 0.0001). Plasma ACE2 was significantly higher in COVID-19 patients with hypertension compared with patients without hypertension (P = 0.0045). Circulating ACE2 was also significantly higher in COVID-19 patients with pre-existing heart conditions and kidney disease compared with patients without these pre-existing conditions (P = 0.0363 and P = 0.0303, respectively). CONCLUSION This study suggests that measuring plasma ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 could be a link between COVID-19 illness severity and its established risk factors hypertension, pre-existing heart disease and pre-existing kidney disease.
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Affiliation(s)
- Tue W. Kragstrup
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
| | | | | | | | - Felice Rivellese
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Arnav Mehta
- Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Marcia B. Goldberg
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Department of Microbiology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Michael R. Filbin
- Department of Emergency Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Per Qvist
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark
- Centre for Genomics and Personalized Medicine, CGPM, Aarhus University, Aarhus, Denmark
| | - Bo Martin Bibby
- Department of Biostatistics, Aarhus University, Aarhus, Denmark
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Circulating Soluble ACE2 and Upstream microRNA Expressions in Serum of Type 2 Diabetes Mellitus Patients. Int J Mol Sci 2021; 22:ijms22105263. [PMID: 34067683 PMCID: PMC8156444 DOI: 10.3390/ijms22105263] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/12/2021] [Accepted: 05/13/2021] [Indexed: 12/13/2022] Open
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic was associated with multiple organ failure and comorbidities, such as type 2 diabetes mellitus (T2DM). Risk factors, such as age, gender, and obesity, were associated with COVID-19 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to use several host receptors for viral entry, such as angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the lung and other organs. However, ACE2 could be shed from the surface to be soluble ACE2 (sACE2) in the circulation. The epigenetic factors affecting ACE2 expression include a type of small non-coding RNAs called microRNAs (miRNAs). In this study, we aimed at exploring the status of the sACE2 as well as serum levels of several upstream novel miRNAs as non-invasive biomarkers that might have a potential role in T2DM patients. Serum samples were collected from 50 T2DM patients and 50 healthy controls, and sACE2 levels were quantified using enzyme-linked immunosorbent assay (ELISA). Also, RNA was extracted, and TaqMan miRNA reverse transcription quantitative PCR (RT-qPCR) was performed to measure serum miRNA levels. Our results revealed that sACE2 is decreased in the T2DM patients and is affected by age, gender, and obesity level. Additionally, 4 miRNAs, which are revealed by in silico analysis to be potentially upstream of ACE2 were detectable in the serum. Among them, miR-421 level was found to be decreased in the serum of diabetic patients, regardless of the presence or absence of diabetic complications, as well as being differential in various body mass index (BMI) groups. The other 3 miRNAs (miR-3909, miR-212-5p, and miR-4677-3p) showed associations with multiple factors including age, gender, BMI, and serum markers, in addition to being correlated to each other. In conclusion, our study reveals a decline in the circulating serum levels of sACE2 in T2DM patients and identified 4 novel miRNAs that were associated with T2DM, which are influenced by different clinical and demographic factors.
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COVID-19 in Patients with Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1318:243-261. [PMID: 33973183 DOI: 10.1007/978-3-030-63761-3_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Hypertension has been listed in several case series and retrospective cohorts as a potential risk factor for the incidence and severity of the new coronavirus (SARS-CoV-2)-associated disease (COVID-19). The debate is noteworthy because almost one billion people around the globe are estimated to have hypertensive diseases, according to the Global Burden of Disease study. Considering the SARS-CoV-2's high infectivity rates, a possible interaction between COVID-19 and hypertension is worrisome. Additionally, antihypertensive drugs, especially the renin-angiotensin-aldosterone system (RAAS) inhibitors, could also influence the natural course of COVID-19 infection. Not only can these associations hold from an epidemiologic standpoint, a mechanistic scenario possibly exists. Hypertension and antihypertensive drugs can increase the expression of transmembrane angiotensin-converting enzyme (ACE)-2 receptors, the entry target of the viruses, thus facilitating infectivity. On the other hand, an increase in ACE-2 could be protective considering the anti-inflammatory, antithrombotic effects of the ACE-2-angiotensin 1-7/Mas pathway. So far, little is known about the whole picture. Observational studies appear to indicate at least a twofold increased risk of mortality for hypertensive patients with COVID-19; however, the previous and continued use of RAAS inhibitors may be protective in this subgroup of patients. The scarcity of randomized clinical trials precludes evidence-based decision-making. At least one randomized study in a non-specified sub-analysis demonstrated no relationship between an angiotensin-converting enzyme inhibitor and incidence or severity of the disease. It is reflected mainly by observational studies and, therefore, by international cardiology societies' guidelines, which state that antihypertensive drugs, particularly RAAS inhibitors, should not be discontinued unless necessary on a case-by-case basis.
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Wiese O, Zemlin AE, Pillay TS. Molecules in pathogenesis: angiotensin converting enzyme 2 (ACE2). J Clin Pathol 2021; 74:285-290. [PMID: 32759311 PMCID: PMC7409947 DOI: 10.1136/jclinpath-2020-206954] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 07/22/2020] [Indexed: 12/14/2022]
Abstract
The renin-angiotensin system is mainly associated with the regulation of blood pressure, but recently many other functions of this system have been described. ACE2, an 805-amino acid monocarboxypeptidase type I transmembrane glycoprotein, was discovered in 2000 and has sequence similarity to two other proteins, namely ACE and collectrin. The ACE2 gene is located on Xp22 and is highly polymorphic. ACE2 is expressed in numerous tissues especially the lung alveolar epithelial cells, heart, kidney and gastrointestinal tract. Animal studies have found that ACE2 is central in diseases affecting almost all organ systems, among other cardiac, respiratory, renal and endocrine functions. ACE2 was identified as the cellular contact point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the global pandemic (COVID-19), and is a potential drug target. SARS-CoV-2 infection has several effects on the renin-angiotensin system and conversely, regulation of this receptor may affect the progress of infection. We describe the genetics and functions of ACE2, explore its various physiological functions in the renin-angiotensin system and discuss its role in the pathophysiology of disease. ACE2 opposes the vasopressor ACE pathway of the renin-angiotensin system by converting angiotensin (Ang) I to Ang (1-9) and Ang II to Ang (1-7) which initiates the vasodilatory pathway. ACE2 may have a protective effect in the lung and kidney as knockout mice display susceptibility to acute respiratory distress and hypertensive nephropathy. Binding of SARS-CoV-2 and the subsequent fusion and downregulation of this pathway during SARS-CoV-2 infection may explain some of the unusual sequelae seen in COVID-19.
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Affiliation(s)
- Owen Wiese
- Division of Chemical Pathology, Faculty of Health Sciences, Stellenbosch University & National Health Laboratory Service (NHLS), Cape Town, South Africa
| | - Annalise E Zemlin
- Division of Chemical Pathology, Faculty of Health Sciences, Stellenbosch University & National Health Laboratory Service (NHLS), Cape Town, South Africa
| | - Tahir S Pillay
- Department of Chemical Pathology, University of Pretoria & National Health Laboratory Service (NHLS), Pretoria, South Africa
- Division of Chemical Pathology, University of Cape Town, Cape Town, South Africa
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Hussain A, Tang O, Sun C, Jia X, Selvin E, Nambi V, Folsom A, Heiss G, Zannad F, Mosley T, Virani SS, Coresh J, Boerwinkle E, Yu B, Cunningham JW, Shah AM, Solomon SD, de Lemos JA, Hoogeveen RC, Ballantyne CM. Soluble Angiotensin-Converting Enzyme 2, Cardiac Biomarkers, Structure, and Function, and Cardiovascular Events (from the Atherosclerosis Risk in Communities Study). Am J Cardiol 2021; 146:15-21. [PMID: 33539861 PMCID: PMC8038970 DOI: 10.1016/j.amjcard.2021.01.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/13/2021] [Accepted: 01/19/2021] [Indexed: 12/13/2022]
Abstract
Membrane-bound angiotensin-converting enzyme 2 is important in regulation of the renin-angiotensin-aldosterone system, but the association of cleaved soluble ACE2 (sACE2) with cardiovascular disease (CVD) is unclear. We evaluated the association of sACE2 with cardiac biomarkers, structure, and function and cardiovascular events in the Atherosclerosis Risk in Communities Study. sACE2 was measured in a subset of 497 participants (mean age 78±5.4 years, 53% men, 27% black); Cox regression analyses assessed prospective associations of sACE2 with time to first CVD event at median 6.1-year follow-up. sACE2 was higher in men, blacks, and participants with prevalent CVD, diabetes, or hypertension. Higher sACE2 levels were associated with significantly higher biomarkers of cardiac injury (high-sensitivity cardiac troponin I and T, N-terminal pro-B-type natriuretic peptide), greater left ventricular mass index, and impaired diastolic function in linear regression analyses, and with increased risk for heart failure hospitalization (adjusted hazard ratio per natural log unit increase [HR] 1.32, 95% confidence interval [CI] 1.10 to 1.58), CVD events (HR 1.34, 95% CI 1.13 to 1.60), and all-cause death (HR 1.26, 95% CI 1.01 to 1.57). In an elderly biracial cohort, sACE2 was positively associated with biomarkers reflecting myocardial injury and neurohormonal activation, left ventricular mass index, impaired diastolic function, CVD, events and all-cause death.
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Affiliation(s)
- Aliza Hussain
- Department of Medicine, Baylor College of Medicine, Houston, Texax; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, Texas
| | - Olive Tang
- Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Caroline Sun
- Department of Medicine, Baylor College of Medicine, Houston, Texax
| | - Xiaoming Jia
- Department of Medicine, Baylor College of Medicine, Houston, Texax
| | - Elizabeth Selvin
- Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Vijay Nambi
- Department of Medicine, Baylor College of Medicine, Houston, Texax; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, Texas; Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Aaron Folsom
- Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota
| | - Gerardo Heiss
- Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina
| | - Faiez Zannad
- French Clinical Research Infrastructure Network Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Université de Lorraine, Nancy, France
| | - Thomas Mosley
- Memory Impairment and Neurodegenerative Dementia Center, University of Mississippi Medical Center, Jackson, Mississippi
| | - Salim S Virani
- Department of Medicine, Baylor College of Medicine, Houston, Texax; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, Texas; Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Josef Coresh
- Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Eric Boerwinkle
- School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
| | - Bing Yu
- School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas
| | - Jonathan W Cunningham
- Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Amil M Shah
- Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
| | - James A de Lemos
- Division of Cardiology, University of Texas-Southwestern Medical Center, Dallas, Texas
| | - Ron C Hoogeveen
- Department of Medicine, Baylor College of Medicine, Houston, Texax; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, Texas
| | - Christie M Ballantyne
- Department of Medicine, Baylor College of Medicine, Houston, Texax; Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, Texas.
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